Ex Parte Johnston et alDownload PDFPatent Trials and Appeals BoardMay 3, 201913624332 - (D) (P.T.A.B. May. 3, 2019) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 13/624,332 09/21/2012 21971 7590 05/07/2019 WILSON, SONSINI, GOODRICH & ROSATI 650 PAGE MILL ROAD PALO ALTO, CA 94304-1050 FIRST NAMED INVENTOR Stephen Albert Johnston UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www .uspto.gov ATTORNEY DOCKET NO. CONFIRMATION NO. 43638-701.401 4051 EXAMINER BUNKER, AMY M ART UNIT PAPER NUMBER 1639 NOTIFICATION DATE DELIVERY MODE 05/07/2019 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): patentdocket@wsgr.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte STEPHEN ALBERT JOHNSTON and PHILLIP STAFFORD Appeal2019-001721 Application 13/624,332 Technology Center 1600 Before FRANCISCO C. PRATS, ULRIKE W. JENKS, and RACHEL H. TOWNSEND, Administrative Patent Judges. JENKS, Administrative Patent Judge. DECISION ON APPEAL Appellants 1 submit this appeal under 35 U.S.C. § 134(a) involving claims directed to an array containing immobilized peptides. Examiner rejected the claims as lacking written descriptive support, as not being enabled, for anticipation, and for obviousness. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 The Appeal Brief lists the Arizona Board of Regents on behalf of Arizona State University, the assignee of record, as the real party in interest. Appeal. Br. 3. We have considered, and herein refer to, the Specification of Dec. 11, 2012 ("Spec."); Final Office Action of Feb. 28, 2018 ("Final Act."); Appeal Brief of Aug. 27, 2018 ("Appeal Br."); Examiner's Answer of Oct. 17, 2018 ("Answer"); Reply Brief of Dec. 17, 2018 ("Reply Br."); and Transcript from the oral hearing held Apr. 4, 2019 ("Tr."). Appeal2019-001721 Application 13/624,332 STATEMENT OF THE CASE Claims 55, 87, 89-91, 94, 95, 98-103, and 112-115 are on appeal, and can be found in the Claims Appendix of the Appeal Brief. Claim 55, representative of the claims on appeal, reads as follows: 55. An array to classify one or more states of health, comprising at least 100,000 different linear, unbranched peptides of between 10-30 natural amino acids in length, each of said at least 100,000 different linear, unbranched peptides having a unique amino acid sequence, each unique amino acid sequence chosen without regard to the identity of a particular target or natural ligand to the target, and each of said at least 100,000 different linear, unbranched peptides having a unique amino acid sequence occupying a distinct feature of the array, wherein each of said at least 100,000 different linear, unbranched peptides are immobilized onto a glass or a silicone surface of the array, and each of said at least 100,000 different linear, unbranched peptides peptides [sic] contain no cysteine residues with the optional exception of a terminal amino acid, wherein each distinct feature of the array comprises at least two peptides of a same amino acid sequence, wherein at least 50 of said at least 100,000 different linear, unbranched peptides have dissociation constants of between 1 mM and 1 µM to at least one antibody in a sample and show a common pattern of binding for a health state of a patient to classify the one or more states of health of the patient, the one or more states of health of the patient including inflammation, cancer and infection, and wherein the array does not include synbodies immobilized on the surface of the array. Appeal Br. 25 (Claims Appendix) 2 Appeal2019-001721 Application 13/624,332 The claims stand rejected2 as follows: I. Claims 55, 87, 89-91, 94, 95, 98-103, and 112-115 under 35 U.S.C. § 112, first paragraph, as failing to comply with the written description requirement. II. Claims 55, 87, 89-91, 94, 95, 98-103, and 112-115 under 35 U.S.C. § 112, first paragraph, because the Specification (1) does not reasonably provide enablement for all arrays comprising at least 100,000 of all different linear, unbranched peptides, (2) for at least 50 peptide having the recited dissociation constants. III. Claims 55, 87, 89-91, 95, 98, 101-103, and 112-115 under 35 U.S.C. § 102(b) as being anticipated by Kodadek3 as evidenced by Lee. 4 IV. Claims 55, 87, 89-91, 94, 95, 98-103, and 112-115 under 35 U.S.C. § I03(a) as unpatentable over Lee in view of Johnston. 5 V. Claims 55, 87, 89-91, 94, 95, 98-103, and 112-115 under 35 U.S.C. § I03(a) as unpatentable over Andresen6 and Chu. 7 2 The filing date of the present application is September 21, 2012, which precedes the America Invents Act (AIA) effective date of March 16, 2013, therefore, we apply pre-AIA 35 U.S.C. §§ 112, 102, and 103 in this opinion. See MPEP § 2159 (Rev. 08.2017). 3 Thomas Kodadek, US 2007/0003954 Al, published Jan. 4, 2007 ("Kodadek"). 4 Frank D. Lee et al., US 2005/0255491 Al, published Nov. 17, 2005 ("Lee"). 5 Stephen A. Johnston et al., WO 2008/048970 A2, published Apr. 24, 2008 ("Johnston"). 6 Reiko Andresen and Carsten Grotzinger, Deciphering the Antibodyome - Peptide Arrays for Serum Antibody Biomarker Diagnostics, 6 CURRENT PROTEOMICS 1-12 (2009) ("Andresen"). 7 Keting Chu, US 2009/0176664 Al, published July 9, 2009 ("Chu"). 3 Appeal2019-001721 Application 13/624,332 Claim Construction We begin with claim interpretation so we can properly compare the scope of the claims to the prior art. "During examination, 'claims ... are to be given their broadest reasonable interpretation consistent with the specification, and ... claim language should be read in light of the specification as it would be interpreted by one of ordinary skill in the art."' In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004)(quotingin re Bond, 910 F. 2d. 831,833 (Fed. Cir. 1990)). Therefore, we first tum to the Specification to interpret the limitations set out in independent claim 5 5. (i) Preamble: An array to classify one or more states of health "If the preamble adds no limitations to those in the body of the claim, the preamble is not itself a claim limitation and is irrelevant to proper construction of the claim." IMS Technology, Inc. v. Haas Automation, Inc., 206 F.3d 1422, 1434 (Fed. Cir. 2000). The preamble in context with the relevant portion of the body of claim 55 reads as follows: An array to classify one or more states of health, wherein at least 50 of said at least 100,000 different linear, unbranched peptides have dissociation constants of between 1 mM and 1 µM to at least one antibody in a sample and show a common pattern of binding for a health state of a patient to classify the one or more states of health of the patient, the one or more states of health of the patient including inflammation, cancer and infection. Appeal Br. 25 (Claims Appendix). Here, the preamble informs us that the array, a structure, is used to classify states of health. The question is does the preamble recitation of "classify[ing] one or more states of health" by 4 Appeal2019-001721 Application 13/624,332 itself limit the claim structurally? See Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1468 (Fed. Cir. 1990) ("[A]pparatus claims cover what a device is, not what a device does."). On this point we agree with Examiner and do not find that this preamble recitation provides structural information; instead, we agree that this recitation describes the intended use of the array. See Ans. 15, 18, 22. "Where ... a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation." Rowe v. Dror, 112 F.3d 473, 478 (Fed. Cir. 1997). As discussed in more detail below (see vii), the one or more states of health is something that is classifiable by the array after applying samples to it and comparing results between different samples. However, it is not itself a structural component of the array. Accordingly, we find that the preamble informs that the claim is directed to an array, a structure, but does not provide any other structural information. (ii) Claim body: comprising at least 100,000 different linear, unbranched peptides of between 10---30 natural amino acids in length, each of said at least 100,000 different linear, unbranched peptides having a unique amino acid sequence Neither Appellants nor Examiner raise any issues with respect to this limitation. Accordingly, we find that this limitation references linear unbranched peptides made up of natural amino acids having a peptide length between 10-30 amino acids. 5 Appeal2019-001721 Application 13/624,332 (iii) each unique amino acid sequence chosen without regard to the identity of a particular target or natural ligand to the target, and each of said at least 100,000 different linear, unbranched peptides having a unique amino acid sequence occupying a distinct feature of the array Examiner has interpreted the term "chosen without regard to the identity of a particular target or natural ligand to the target" to encompass "any method of choosing peptide sequences, including computer generation/selection, mental selection, random selection etc." Ans. 4. Examiner has interpreted the term "having a unique amino acid sequence" as referring "to any level of diversity of structure and/or sequence, including any change in length and/ or structure by one or more amino acids of the array such as the addition/removal of a protecting group, a single variation, a single addition, single deletion and/or a single difference in an amino acid or monomer of the peptide sequence." Ans. 4. Appellants emphasize that "the disclosure provides for arrays that are not disease or condition specific." Appeal Br. 13. Specifically, Appellants contend that the amino acids are chosen without regard to a particular target or natural ligand. See Ans. 21. In other words, the peptides are chosen and not selected based on any particular disease epitopes. See Tr. 7-8. The Specification discloses that the production of the peptide micro arrays utilizes software. Spec. ,II 40. "A library chosen by random selection, once selected is of known identity and can be reproduced without repeating the initial random selection process." Spec. ,r 49. Here, each peptide sequence in the array was originally randomly selected using software, however, this does not mean that the peptide located in each feature (i.e. dot) on the array is unknown. 6 Appeal2019-001721 Application 13/624,332 Therefore, this limitation is interpreted to refer to the selection of the unique structure of a peptide that is placed onto the array, that selection must be random and each randomly selected unique peptide is placed on a distinct dot ("feature") on the array. That is the random process of selecting a linear, unbranched peptide of between 10-30 natural amino acids in length is repeated for each of the 100,000 unique peptides that are placed onto different dots on the array. (iv) wherein each of said at least 100,000 different linear, unbranched peptides are immobilized onto a glass or a silicone surface of the array The Specification suggests numerous materials that can be used for the array and these materials include glass and silicone surfaces. Spec. ,r 61. Therefore, this limitation is interpreted to describe the substrate that receives the peptides, and the substrate encompasses glass or silicone. (v) each of said at least 100,000 different linear, unbranched peptides peptides [sic] contain no cysteine residues with the optional exception of a terminal amino acid The Specification provides: A microarray is prepared by robotically spotting distinct polypeptides [of20 amino acids in length] on a glass slide having an aminosilane functionalized surface. Each polypeptide has a C-terminal glycine-serine-cysteine as the three C-terminal residues and the remaining ( 1 7) residues determined by a pseudorandom computational process in which each of the 20 naturally occurring amino acids except cysteine had an equal probability of being chosen at each position. . . . The concentration of peptide or other compound determines the average spacing between peptide molecules within a region of the array. Spec. ,r 62. 7 Appeal2019-001721 Application 13/624,332 Examiner has interpreted the limitation "contain[ s] no cysteine residues" to "refer to the exclusion of all cysteines in the peptide except for an optional C-terminal cysteine which provides a point of attachment of the peptide to the support." Ans. 4. Appellants does not dispute this interpretation. Therefore, this limitation is interpreted to refer to the amino acid structures making up the peptides in the array and cysteine, if present, is only located at the C-terminal position of a peptide. (vi) wherein each distinct feature of the array comprises at least two peptides of a same amino acid sequence Examiner has interpreted the combination of "each of the different peptides having a unique sequence ... and each of the different peptides occupying a distinct feature of the array," and "wherein each distinct feature of the array comprises at least two peptides of the same sequence" to refer to 100,000 different peptides on the array having a unique sequence. Although the term "feature" is not specifically defined in the Specification, Appellants contend that this is a term of art and describes the surface area occupied by a peptide on the array. 8 The Specification explains 8 During oral argument, Appellants counsel clarified that a "feature" is a term of art in the array field that describes a particular spot on the array that contains a single attached protein. See Tr. 6: 12-14 ("So a feature is considered to be a distinct physical space within the array. Within that feature, you have peptides of the same sequence"); see also Appeal Br. 7 ("i.e. each feature of the array is occupied only by molecules of the same peptide"). Although we do not find a definition in the Specification that defines "feature," the Specification and the claims reasonably describe that a feature is referencing a particular area on the array substrate. Compare claim 55 recitation of "each of said at least 100,000 different linear, unbranched peptides having a unique amino acid sequence occupying a distinct feature of the array" with claims 55 recitation "wherein each distinct feature of the array comprises at least two peptides of a same amino acid 8 Appeal2019-001721 Application 13/624,332 that "polypeptides are chemically synthesized ... , and then diluted 4: 1 with phosphate buffered saline prior to spotting [ onto the array substrate]. The concentration of peptide or other compound determines the average spacing between peptide molecules within a region of the array." Spec. ,r 62. We find that the "feature" limitation when read in the context of the claim in light of the Specification as understood by one of ordinary skill in the art to describe an area on the array to which the peptide is attached. The Specification discloses that multiple molecules can be attached to a particular area of the array. See Spec. ,r 62. The Specification describes that a particular spot size will have a particular spot area that can then receive a certain number of peptides within that area. See Spec. ,r 63 ("An exemplary calculation of spacing is as follows: spot size: 150 µm, spot area: 17 671 µm2, nanoprint deposition volume."). Accordingly, we find that "feature" as recited in the claims describes a region (i.e., area or dot) on the array that can bind a particular compound. The limitation, therefore, is interpreted to be referencing an area on the array surface to which multiple peptides having the same amino acid sequence are attached. sequence;" see also Spec. ,r 62 ("The polypeptides are chemically synthesized, dissolved in dimethyl formamide ... , and then diluted 4: 1 with phosphate buffered saline prior to spotting [the peptide onto the array surface]. The concentration of peptide or other compound determines the average spacing between peptide molecules within a region of the array."). Accordingly, we find that "feature" as recited in the claims reasonably describes a particular surface area (i.e. dot) on the array. 9 Appeal2019-001721 Application 13/624,332 (vii) wherein at least 5 0 of said at least 100,000 different linear, unbranched peptides have dissociation constants of between 1 mM and 1 µM to at least one antibody in a sample and show a common pattern of binding for a health state of a patient to classify the one or more states of health of the patient, the one or more states of health of the patient including inflammation, cancer and infection. Examiner, in the Answer, parses this limitation into two phrases that each need interpretation. For the art rejection, Examiner interprets the part of the limitation requiring the ability of 50 or more unbranched peptides exhibiting the claimed dissociation constant to at least one antibody to classify the one or more states of health as being an intended use limitation (see Ans. 33). For the enablement rejection, Examiner interprets the part of the limitation regarding the fact that at least 50 of said at least 100,000 different linear, unbranched peptides have dissociation constants of between 1 mM and 1 µM to at least one antibody in a sample to require recitation of the structures of the peptides that are placed onto the support. We address these interpretations below: (a) to determine dissociation constants of antibody in a sample requires knowledge of the peptide structure For the enablement rejection, Examiner takes the position that in order to satisfy this particular claim limitation the Appellants must "provide adequate description of such core structure and function related to that core structure such that the Artisan could determine the desired effect." Ans. 6- 7. Examiner specifically points out that the Specification does not provide any dissociation constants for any peptides. See Ans. 7. Examiner therefore questions whether an array containing 100,000 different linear peptides would contain sequences that meet the recited dissociation constant to at least one antibody. See Ans. 8. Examiner's position is that unless you 10 Appeal2019-001721 Application 13/624,332 disclose the structures of peptides that are put onto the array it would not be possible to determine whether "all samples from all patients, in all combinations" contain antibodies that would meet the recited dissociation constant. At the oral hearing, Appellants council explained that when 100,000 different peptides are printed onto an array substrate where the peptide density at every one of the features does not exceed 6 nm, any serum sample is expected to contain at least one antibody that would bind to at least 50 of the immobilized different peptides within the recited low binding constant range. 9 There is an expectation that at least 50 spots would inherently meet the recited dissociation constants in an array having 100,000 different peptide features provided the high local concentration of peptide in each 9 During oral argument, Appellants' counsel explained that when you have an array of 100,000 peptides within the size range claimed there is an expectation that at least 50 of those peptides will bind to an antibody from a patient sample at the recited low affinity. See Tr. 14 ("when you have enough peptides, and here, the enough peptides is the 100,000 different linear unbranched peptides, and it's also the amino acid length of the peptides themselves ... The applicants know that they're going to have peptides that are not going to bind as strong to the antibody, but it [still] gives valuable information. It's something that the inventors needed to have in order to be able to discriminate the diseases."). This interpretation is reasonably supported in the Specification. See Spec. ,r 74; see also ,r 45("The number of compounds is a balance between two factors. The more compounds, the more likely an array to include members having detectable affinity for any target of interest. . . . Therefore, a relatively small number of peptides can provide a good representation of total sequence space, and include members capable of specific albeit low affinity interactions with a wide variety of targets. For example, 500-25,000 random peptides can cover evenly the entire shape space of an immune system (107 to 108 antibodies in humans)."). 11 Appeal2019-001721 Application 13/624,332 feature is a defined as explained in the Specification. See Tr. 14. For purposes of this appeal, we determine that the recited binding dissociation limitation imparts a structural requirement to the array. That requirement is a spacing limitation at each distinct feature of the at least two peptides, namely the at least two peptides must be spaced apart from each other at a mean average spacing of no greater than 6 nm. See Spec. ,r 55. (b) classifying the one or more states of health of the patient is an intended use limitation The Specification explains that a state of health is determined by comparing "binding profiles of normal volunteers, Breast Cancer patients, and patients at risk of breast cancer who clinically have had a second, different primary tumor following an initial remission of Breast Cancer." Spec. ,r 27 ( citing Figure 7). "For example, the binding profile can be compared with binding profiles known to be associated with different diseases or stages of diseases or lack of diseases .... Remarkably, the same array can generate different and informative profiles with many different samples representing different disease states, disease stages, lack of disease and the like." Spec. ,r 43. "Another application lies in analyzing samples from vaccinated patients to determine whether an adequate protective immune response is developing. The pattern of response in one patient can be compared, for example, with a patient who has been naturally infected with the pathogen and survived, a similarity of response pattern indicating the patient is likely to survive and a dissimilarity that the patient will get worse or die at least in the absence of alternate treatment." Spec. ,r 77. In other words, in order to determine a patient's state of health, the Specification explains that this requires making a comparison between at least two samples. The samples could encompass different patient 12 Appeal2019-001721 Application 13/624,332 populations, e.g., normal healthy patients versus those suspected of having a disease; it could also encompass a comparison between samples taken from the same patient at different points in time (i.e. before or after vaccination to determine if there is an immune response). Thus, for an array to "classify one or more states of health" requires a process step that compares the results between different samples using at least two arrays side-by-side. Because the limitation of "classify[ing] one or more states of health" as recited in the claim refers to the way the array is used, we agree with the Examiner that this limitation is directed to the use of the array and does not affect the structure of how the peptides are attached to each distinct feature of the array. See above fn. 8. (viii) wherein the array does not include synbodies immobilized on the surface of the array The Specification provides that "arrays can include other compounds known to bind particular targets, such as proteins, in a sample. These compounds can be antibodies, synbodies or peptides among others." Spec. ,r 64. This limitation is interpreted to specifically exclude one particular type of compound, namely synbodies, from the array. Conclusion Based on the interpretation of each limitation as discussed above, the array as recited in claim 55 has the following structural limitations: (1) contains at least 100,000 distinct features (i.e. dots or areas) to which peptides are attached on the substrate; (2) each feature contains a peptide of only a single sequence structure and it is a different amino acid sequence from every other feature; (3) the peptides are immobilized onto a glass or silicone substrate; ( 4) the peptide does not contain cysteine residues with the 13 Appeal2019-001721 Application 13/624,332 exception of terminal cysteine used to attach the peptide to the substrate; ( 5) the peptides are linear unbranched peptides; ( 6) each feature contains at least two peptides having the same amino acid sequence; (7) because the array must have at least 50 of the peptides meet the recited dissociation constant if contacted with a patient sample, the mean average space between the peptides in a single feature is 6 nm or less; and (8) the array does not contain synbodies. I. Written Description Examiner finds that the claims contain subject matter that is not described in the Specification in such a way that it would reasonably convey that one skilled in the art would understand that inventor had possession of the claimed invention. Ans. 5-6. Specifically, Examiner finds that adequate description requires providing "core structure [information] and function related to that core structure" so that one of ordinary skill could determine that the array has the desired effect. Ans. 6-7. Examiner notes that Appellants working example only disclose an array with peptide concentrations of 1 mg/ml and having only 10,000 peptides, with no dissociation constants disclosed, and undisclosed peptides. See Ans. 7. Examiner cites Balboni, 10 Gao, 11 Andresen, and Hilpert 12 as evidence "that not all microarrays comprising all random peptides having any structures 10 Balboni et al., Multiplexed Protein Array Platforms for Analysis of Autoimmune Diseases, 24 ANNU. REV. IMMUNOL. 391--418 (2006)("Balbone"). 11 Gao et al., High density peptide microarrays. In situ synthesis and applications, 8 MOLECULAR DIVERSITY 177-187 (2004)("Gao"). 12 Hilpert et al., Cellulose-bound Peptide Arrays: Preparation and Applications, 24 BIOTECH. GENETIC ENG. REV. 31-106 (2007)("Hilpert"). 14 Appeal2019-001721 Application 13/624,332 and/or all concentrations will function to bind at least one of all antibodies in all samples from all patients, such that all states of health in all patients can be classified." Ans. 8. Because of the limited information in the Specification, Examiner finds that the written descriptive support is not sufficient to convey that inventor was in possession of arrays having 100,000 peptides attached. See Ans. 9. Appellants direct our attention to the various experimental protocols disclosed in the Specification. Specifically, citing example 3 which shows the use of the arrays with "samples from about 200 cancer patients having various kinds of cancer including glioma, sarcoma, and pancreatic clustered together." Appeal Br. 12. Appellants direct our attention to the various examples that show different binding patterns with patients having different states of health. Appeal Br. 12-13 (citing examples 3, 5, and 6, as well as figures 5 and 6). Appellants contend that "the disclosure provides for arrays that are not disease or condition specific." Appeal Br. 13. We find Appellants have the better position. As discussed in the claim construction section above, the array as recited in claim 55 is directed to a structure that (1) contains at least 100,000 distinct features (i.e. dots or areas) to which peptides are attached on the substrate; (2) each feature contains a peptide of only a single sequence structure and it is a different amino acid sequence from every other feature; (3) the peptides are immobilized onto a glass or silicone substrate; ( 4) the peptides do not contain cysteine residues with the exception of terminal cysteine used to attach the peptide to the substrate; ( 5) the peptides are linear unbranched peptides; ( 6) each feature contains at least two peptides having the same amino acid sequence; (7) because the array must have at least 50 peptides 15 Appeal2019-001721 Application 13/624,332 that meet the recited dissociation constant if contacted with a patient sample, the mean average space between the peptides in a single feature is 6 nm or less; and (8) the array does not contain synbodies. In other words, the claims are directed to a product - an array - with specific structural features including with regard to (a) the total number of dots on the array, (b) the types of peptides that are printed on those dots, and thus, the number of different peptides printed on the array, ( c) how many such peptides are printed within a dot, and ( d) the spacing of the peptides within the dot. Examiner's written description rejection, however, is directed to the functioning and use of the array rather than to the structure of the array as claimed. The rejection questions whether the array can achieve the binding constants as recited when the array is in use. See Ans. 7 ("no dissociation constants were provided"). Examiner relies on Hilpert as evidencing the difficulty of finding the right concentration for attaching peptides to a slide. Hilpert teaches that when peptides are attached to the array at a high density this can cause difficulties in assessing interaction with the molecule of interest. Hilpert 34. Even if packing peptides onto a substrate at a high density can have a negative effect on the functional interaction with a specific antibody, this does not raise doubt that the peptide can be successfully attached to the array substrate. Examiner also questions whether an array with random peptides can function to bind at least one antibody in all samples. Ans. 8. Examiner acknowledges that the Specification provides attaching 10,000 peptides that are 20 residues in length onto a glass slide. See Ans. 7. It is not clear, however, why Examiner would doubt that one of ordinary skill in the art could not attach more peptides, for example 90,000 more 16 Appeal2019-001721 Application 13/624,332 peptides onto the array, or that one of ordinary skill could attach peptides that are 30 amino acids in length instead of the 20 amino acid length as disclosed in the Specification. To the extent that there might be a concern by the Examiner that one of ordinary would not be able to replicate a particular array, the Specification explains that software was utilized to provide random sequences for the first 1 7 positions ( where the amino acids were chosen from 19 naturally occurring amino acids and not including cysteine) of a 20- residue peptide and having the three carboxy terminal amino acids glycine- serine-cysteine as the carboxy-terminus linker. Spec. ,r 140. The Specification further explains that "[a] library chosen by random selection, once selected is of known identity and can be reproduced without repeating the initial random selection process." Spec. ,r 49. In other words, the random aspect of the array is only in the initial selection of the unique peptides that are applied to each dot. Thus, each dot in the array contains a peptide whose structure is known in order to re-produce the array. See Spec. ,r,r 49, 62. Examiner contends that "it is not known whether an array of 100,000 different linear, unbranched peptides of 10 amino acids in length will bind to the same antibodies to produce the same common pattern of binding as a different array of 100,000 different, linear unbranched peptides of 30 amino acids in length, such that all states of health are classified in samples from all subjects." Ans. 26. It appears that the Examiner's rejection interprets that each array slide is different. Here, the Specification is clear that the random aspect of the peptide is only with respect to the selection of the initial peptide. See Spec. ,r,r 49, 62, 140. Once the peptide has been randomly 17 Appeal2019-001721 Application 13/624,332 generated by the computer, it is then produced so that it can be printed onto a slide, and the peptide is known and thereby the slide can be reproduced without needing to repeat the random selection process. See Spec. ,r 49. Thus, the Specification is not contemplating using different randomly created slides in order to determine a state of health in a patient but, instead, is using slides that are identical for comparison between a patient and a healthy cohort or a patient sample over time to determine a state of health. The evidence of record does not support Examiner's position that the written descriptive support provided in the Specification is insufficient to describe the full scope of the array as presently claimed. Accordingly, we reverse the written description rejection. II. Enablement Examiner finds that the Specification does not reasonably provide enablement for all arrays comprising at least 100,000 of different linear unbranched peptides having a unique sequence. Ans. 9-10. Examiner finds that undue experimentation would be required in order to determine dissociation constants for at least 50 of the 100,000 different linear sequences. Ans. 13. Examiner finds that the Specification teaches 10,000 random peptides spotted onto glass slides, and there is no indication that an array with 100,000 different peptides would produce the same result. See id. at 27. Appellants contend that the Specification provides ample guidance in pre-synthesizing peptides that are then spotted onto an array. See Appeal Br. 14. Appellants contend that the disclosure specifies various methods to determine the relative binding of the sample to the array. Id. 18 Appeal2019-001721 Application 13/624,332 It is not clear from Examiner's enablement rejection whether Examiner questions the ability to bind 100,000 peptides onto an array support surface or whether Examiner questions the binding constant of peptides that are part of the array. Either way, we are not persuaded by Examiner's position. We agree with Appellants that the Specification provides ample guidance with respect to the manufacture and classifying multiple conditions using an array. Appeal Br. 14 (citing Spec. ,r,r 51-64, 98-1-1, 0121, and 122); see Reply Br. 12. As Appellants point out "the specification describes that peptides can be pre-synthesized and spotted onto an array." Spec. ,r 51. The issue appears to be that Examiner doubts that a random set of peptides provided on an array with the required structural features noted above would bind at least one antibody in a sample at the recited binding affinity. The Specification explains that "the same array can generate different and informative profiles with many different samples representing different disease states, disease stages, lack of disease and the like." Spec. ,r 43. The Specification explains that the binding profile of a sample is compared "with binding profiles known to be associated with different diseases or stages of diseases or lack of diseases." Spec. ,r 43. In this case, the same array is used to compare a binding profile from a patient with known samples. It is the comparison to the known sample that allows for determination of a disease state. Dissociation constants of between 1 mM and 1 µM to at least one antibody as presently claimed are considered low affinity binding events. See Spec. ,r 43. Appellants direct our attention to Dr. Woodbury's declaration that describes that "[i]t was surprising to us that the array format 19 Appeal2019-001721 Application 13/624,332 of the claims captured informative lower affinity binding events." See Woodbury Dec. 13 ,r 7. During oral argument Appellants' counsel explained that by placing 100,000 different peptides of the claimed amino acid length onto an array surface each on a different one of a 100,000 spots, and also having more than one identically structured peptide in that same spot at a certain maximal mean average distance and exposing that surface to a serum sample, it would be expected that at least 50 of the dots would bind at least one antibody from the sample at the low dissociation constant of between 1 mM and 1 µM. See above fn 8. In other words, an array that contains 100,000 randomly select peptides would be expected to have at least 50 peptides that react with at least one antibody from any patient sample at a dissociation between 1 mM and 1 µM. See Spec. ,r 93 (Example 1 ( citing Figure 1, and Figure 12), noting that this phenomena occurs when even just 10,000 different peptides of the claimed amino acid length were used). Different binding patterns of monoclonal and polyclonal antibodies to different peptides is also observed with these arrays, and many antibodies bind more than one peptide on the array. See Spec. ,r,r 32, 93, 94 (citing Figures 11 and 12). The evidence of record does not support Examiner's position that the Specification fails to provide an enabling disclosure for the scope of the claims as presented. Accordingly, we reverse the enablement rejection. III. Anticipation by Kodadek Examiner finds that Kodadek teaches an array containing synthetic molecules. Ans. 14--16. "Kodadek teaches that a robotic spotter is used to 13 Declaration by Dr. Neal Woodbury signed June 7, 2016 ("Woodbury Dec."). 20 Appeal2019-001721 Application 13/624,332 print the molecules onto the chemically modified glass slide ( corresponding to glass surface; and spotting onto an array, claim 96) (paragraph [0043], lines 6-8)." Ans. 15. "Kodadek [also] teaches that the peptides can be synthesized on a solid support in accordance with conventional techniques (corresponding to being synthesized onto the surface) (paragraph [0075], lines 3-5)." Id. Appellants argue that not every element of the claimed invention is disclosed by the reference (Appeal Br. 15), that "the peptides [in Kodadek] are chosen with regard to the identity of a particular target pathway, disease or organism" (id. at 15), and that Kodadek disavowed the use of a peptide array (id. at 16). In an anticipation rejection, "it is not enough that the prior art reference ... includes multiple, distinct teachings that [ an ordinary] artisan might somehow combine to achieve the claimed invention." Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1371 (Fed. Cir. 2008). To anticipate, Kodadek would need to "clearly and unequivocally" disclose a composition meeting all the limitations of the claims. In re Arkley, 455 F.2d 586, 587 (CCP A 1972). That requirement does not mean that the claimed invention must be described in Kodadek in ipsissimis verbis, In re Schaumann, 572 F .2d 312, 317 (CCP A 1978), but the description in Kodedek must be "sufficient to put the public in possession of the invention." In re LeGrice, 301 F.2d 929, 933 (CCPA 1962). That is not the case here. Kodadek teaches a method of constructing an array to "provide a platform for the determination of 'immune signatures.' This refers to the pattern of binding of antibodies or T cells to an array of synthetic compounds." Kodadek ,r 22. Kodadek teaches that the pattern of binding 21 Appeal2019-001721 Application 13/624,332 can be predictive of a disease state or it can differentiate between disease states. Id. ,r 14. The method includes: (a) constructing an array of synthetic molecules having a plurality of structures; (b) contacting said array with a complex biological mixture obtained from animals or cells that exhibit a physiological state of interest, resulting in the capture of certain biological molecules or cells by certain molecules immobilized on the array; ( c) assessing binding of certain captured molecules or cells to this array through the use of a labeled reagent that binds specifically to a given class of captured molecules or proteins; and ( d) comparison of this binding pattern with the binding pattern of an appropriate control sample that does not represent the physiological state of interest. Kodadek ,r 11. Kodadek teaches that the binding elements may be synthetic peptides or peptoids. Id. ,r 73. Peptides range in length from about 6 up to about 35 to 50 amino acids polypeptide(s), proteins. Id. ,r 75. Kodadek teaches that one or more binding elements can be immobilized on the support surface, and can range in number from 2-100,000 different sensing elements. Id. ,r 66. Kodadek teaches that the binding elements are immobilized on supports including for example: glass (e.g., a chemically-modified glass slide), latex, plastic, membranes, microtiter, wells, mass spectrometer plates, beads ( e.g., cross-linked polymer beads) or the like. Id. ,r 87. Kodadek teaches using a "C-terminal cysteine residue ... to facilitate coupling to the array surface." Id. i-fl33. We do not agree with Appellants that Kodadek does not encompass peptides that are chosen without regard to the target. Appeal Br. 15. Here, Kodadek teaches that "a ligand may be wholly random, partially random, biased or non-biased." Kodadek. ,r 65. A ligand that is randomly generated 22 Appeal2019-001721 Application 13/624,332 would reasonably meet the limitation of "chosen without regard to the identity of a particular target" as claimed. We also do not agree with Appellants that the prosecution history of Kodadek disavowed the use of a peptide array. Appeal Br. 16. The excerpt cited by Appellants are directed to the prosecution of different claims and at best establish that peptides and peptoids are structurally different molecules. Identifying structural differences between peptides and peptoids that may affect their binding to antibodies is not a disavowal of the use of peptides on an array. We do, however, agree with Appellants that Kodadek does not disclose every limitation of the claims. Specifically, Kodadek does not affirmatively teach excluding cysteine residues in all positions but the terminal C-terminal residue. Kodadek suggests that "[a] C-terminal cysteine residue was included in each molecule to facilitate coupling to the array surface." Kodadek ,r 133. A teaching that the C-terminal residue was included for the purpose of attaching the peptide to a substrate may render the exclusion of cysteine residues in other parts of the molecule obvious for purposes of controlling the attachment of the peptide to the slide but it does not necessarily and inevitably indicate Kodadek teaches excluding cysteine from other parts of the peptide. In fact, we note that Kodadek contemplates synthesizing peptide on a solid support, as such excluding incorporating cysteine into such peptides at positions other than the link to the solid support is not a necessity. See Kodadek ,r 75; see Transcript 22 ("Unless you're adding on and you're doing in situ chemistry" then you could have cysteine incorporated into the peptide). The evidence of record does not support the position that Kodadek excludes cysteine residues from all but the 23 Appeal2019-001721 Application 13/624,332 terminal amino acid and thereby anticipates claim 55. Accordingly, we reverse the rejection of claim 55 and any of it depends. 14 IV. Obviousness over Lee and Johnston Examiner finds that Lee teaches an array containing a collection of polypeptide analytes generated by fragmentation of a protein in order to generate peptides that are 5-30 amino acids in length. Ans. 17. Lee "teach[ es] a method of characterizing a plurality of candidate antibodies for binding affinity." Id. at 18. Examiner finds that Lee's arrays can comprise up to 100,000 distinct locations. Id. at 17. Examiner acknowledges that Lee does not teach amino acids omithine and norleucine. Id. at 19. Examiner relies on the teachings of Johnston for teaching "synthetic amino acids [that] include ornithine and norleucine to convey special properties." Id. Appellants contend that "Lee's array includes all possible amino acids within the peptide sequences, including cysteine." Appeal Br. 18. Appellants contend that the structure disclosed in Johnson is directed to synbodies - a structure specifically excluded by the claims. Id. at 17. On this record we find Appellants have the better position. "[E]xaminer bears the initial burden, on review of the prior art or on any other ground, of presenting a prima facie case of unpatentability." In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). In satisfying this initial burden, "[i]t is impermissible to use the claimed invention as an instruction 14 We also agree with Appellants position (see Appeal Br. 16) that the Examiner has not sufficiently established that Kodadek even if viewed in combination with Lee discloses the average spacing of the peptides as being 1--4 nm apart as recited in claims 99 and 100. 24 Appeal2019-001721 Application 13/624,332 manual or 'template' to piece together the teachings of the prior art so that the claimed invention is rendered obvious." In re Fritch, 972 F.2d 1260, 1266 (Fed. Cir. 1992). Stated differently, to establish obviousness, there must be "an apparent reason to combine the known elements in the fashion" recited in the claims. KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,418 (2007). Lee creates arrays from fragmentation of larger proteins; hence, the arrays would include peptides containing cysteine in other locations. See Lee ,r,r 129, 166, 168; see Appeal Br. 18. Johnston teaches spotting between 500-1,000,000 test polypeptides that are 20 amino acids long onto a slide. Johnston 18: 15-16. Johnston teaches that "the polypeptides can be attached to the surface through the C-terminus. The sequence of the polypeptides was generated randomly from 19 amino acids, excluding cysteine." Id. 18: 16-18. However, as Appellants point out Johnston's arrays are directed at synthetic antibodies a structure that is specifically excluded from the present claims. Reply Br. 17. Thus, "Johnston fails to cure deficiencies of Lee at least because Johnston also fails to teach arrays constructed with different linear, unbranched peptides of between 10-3 0 natural amino acids in length occupying a distinct feature of the array." Id. at 18; see Appeal Br. 18-19. Here, Examiner's prima facie case is premised on finding that Lee teaches all the limitations recited in claim 55, and is only relying on Johnson for teaching the synthetic amino acids omithine and norleucine as recited in claim 94. See Ans. 17-19. Examiner in the Answer changes the rejection and now directs our attention to Johnson's teaching as encompassing arrays that contain randomly generated sequences of 19 amino acids, specifically 25 Appeal2019-001721 Application 13/624,332 excluding cysteine, and using a pseudorandom computational process to arrive at the various peptides. See Ans. 31. Examiner however has not explained how or why one of ordinary skill in the art would go from Lee's arrays derived from fragmentation of proteins (Lee ,r,r 45, 49, 115, 126, 140, 221, 243, 315, 317) that would contain cysteine to using Johnston's protocol of creating an array. Johnston 18: 12-26. Specifically, Examiner has not explained why one of ordinary skill in the art would use only part of Johnston's protocol to create synthetic peptides, i.e., the part of creating the linear peptide, and omit the creation of the synbody as taught in Johnston. In other words, just because the reference could possibly be dissected to contain individual elements that could be combined to arrive at the present claims does not mean that the Examiner has provided a sufficiently articulated rationale to do so. A rejection for obviousness must include "articulated reasoning with some rational underpinning to support the legal conclusion." KSR Int'! Co. v. Teleflex Inc., 550 U.S. at 418, quoting In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). Because Examiner has not provided adequate evidence in conjunction with sound technical reasoning to establish that one of ordinary skill would arrive at the array as claimed based on the combined teaching of Lee and Johnston, we reverse the rejection under 35 U.S.C. ,r 103. V. Obviousness over Andresen and Chu Examiner finds that Andresen teaches analysis of antibodies from human serum. Ans. 20. Examiner finds that Andresen also teaches synthetic peptide arrays in varying density formats, having peptides between 8-13 amino acids in length that can be used to fingerprint circulating 26 Appeal2019-001721 Application 13/624,332 antibodies. Id. at 20-21. Examiner acknowledges that Andresen "do[es] not teach wherein each distinct feature of the array comprises at least two peptides of the same sequence (instant claim 55, in part); or the synthetic amino acids omithine or norleucine (instant claim 94); or where the sample is cerebrospinal fluid (instant claim 115)." Ans. 23. Examiner relies on Chu for teaching ultra-high density arrays for high throughput screening. Ans. 24. Examiner finds that Chu teaches "artificial peptides can include randomly synthesized peptides; and peptide arrays with random peptide sequences (corresponding to random peptides) (paragraphs [0095], lines 5-7; and [0129])." Ans. 37. Appellants contend that neither Andresen nor Chu disclose arrays with targets that are not preselected (Appeal Br. 20), and that Chu's substrates are selected form a peptidase database that contain cysteine residues (id. at 21 ). Andresen teaches peptide arrays including describing various ways of covalent and non-covalent site-specific immobilization of peptide. Andresen 4 (see Figure 2). Andresen teaches that "short synthetic peptides can be used as probes to specifically detect antibodies from complex biological fluid." Id. at 5. Andresen teaches "peptide arrays for the identification of antibody reactivities by using a relatively small library of 5520 random peptides to identify epitopes of four monoclonal antibodies." Id. Chu teaches that enzymatic substrates include "artificial peptides[,] can include randomly synthesized peptides, peptides designed based on physiological substrates, and peptides designed based on the structure or known binding of enzymes. In some embodiments, the peptide array can be 27 Appeal2019-001721 Application 13/624,332 a mix of artificial and physiological substrates." Chu ,r 95. Chu teaches that protease substrates are disclosed in peptide databases. Id. ,r 101. On this record, we find Appellants have the better position. Examiner has not directed us to teachings in the combination of Andersen and Chu that would lead us to conclude that the peptide arrays disclosed in these references necessarily omit cysteine from the peptides in their array. Examiner has not articulated any other rationale explaining how the combination of references discloses an array that does not contain cysteine as claimed. Accordingly, we are constrained to reverse the rejection that relies on the combination of Andresen and Chu. SUMMARY We reverse the rejection of all claims on all grounds. REVERSED 28 Copy with citationCopy as parenthetical citation