Children's Hospital Medical Center

Patent Trials and Appeals BoardAug 3, 2020

2019006072 (P.T.A.B. Aug. 3, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE 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 APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 15/430,815 02/13/2017 Gregory A. Grabowski 0010872.0644711 7501 26874 7590 08/03/2020 FROST BROWN TODD LLC 3300 Great American Tower 301 East Fourth Street Cincinnati, OH 45202 EXAMINER SAIDHA, TEKCHAND ART UNIT PAPER NUMBER 1652 NOTIFICATION DATE DELIVERY MODE 08/03/2020 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): patents@fbtlaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ________________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ________________ Ex parte GREGORY A. GRABOWSKI and HONG DU1 ________________ Appeal 2019-006072 Application 15/430,815 Technology Center 3600 ________________ Before ULRIKE W. JENKS, JOHN G. NEW, and RYAN H. FLAX, Administrative Patent Judges. NEW, Administrative Patent Judge. DECISION ON APPEAL 1 We use the term “Appellant” to refer to the “applicant” as defined in 37 C.F.R. § 1.142. Appellant identifies Children’s Hospital Medical Center as the real party in interest. Appeal Br. 3. Appeal 2019-006072 Application 15/430,815 2 SUMMARY Appellant files this appeal under 35 U.S.C. § 134(a) from the Examiner’s Final Rejection of claims 45–47 as unpatentable under 35 U.S.C. § 101 as being directed to nonstatutory subject matter.2 Claims 45–47 also stand rejected as unpatentable under 35 U.S.C. § 103(a) as being obvious over the combination of over R.A. Anderson et al., Cloning and Expression of cDNA Encoding Human Lysosomal Acid Lipase/CholesteryI Ester Hydrolase: Similarities to Gastric and Lingual Lipases, 266(39) J. BIOL. CHEM. 22479–84 (1991) (“Anderson”) and Louderback (US 4,325,832, April 20, 1982) (“Louderback”) or Xiao (US 2004/0038365 A1, February 26, 2004 (“Xiao”). We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. NATURE OF THE CLAIMED INVENTION Appellant’s claimed invention is directed to a method to diminish and/or eliminate atherosclerotic plaques, in mammals, through direct and indirect treatment of these plaques, in situ, using substances capable of lipid removal, primarily through hydrolysis. Abstr. REPRESENTATIVE CLAIM Claim 45 is representative of the claims on appeal and recites: 2 Claims 1, 31, 32, 34–36, 38–40 and 42–47 are pending in Appellant’s application and currently stand rejected. See Final Act. 6. However, only claims 45–47 are presently on appeal. App. Br. 5. Appeal 2019-006072 Application 15/430,815 3 45. A sterile, aqueous solution consisting of a) human lysosomal acid lipase (hLAL) protein; b) human serum albumin; c) one or more buffers; and d) water App. Br. 14. ISSUES AND ANALYSES We decline to adopt the Examiner’s conclusion that the claims on appeal are directed to nonstatutory subject matter, or that the claims are prima facie obvious over the combined cited prior art. We address the arguments raised by Appellant below. A. Rejection of clams 45–47 under 35 U.S.C. § 101 Issue Appellant argues that the Examiner erred in finding that the claims are directed to an abstract idea and, therefore, are patent-ineligible subject matter.3 App. Br. 17. 3 Appellant argues that the Examiner concluded that the claims on appeal recited an “abstract idea,” however, it is evident from the Examiner’s reasoning in the Final Action that the Examiner concluded that the claims recite a product of nature, and are therefore a judicial exception to § 101. See Final Act. 8–9. Appeal 2019-006072 Application 15/430,815 4 Analysis The Examiner finds that claims 45–47 recites a sterile, aqueous composition comprising: (1) human lysosomal lipase (hLAL); (2) human serum albumin; (3) one or more buffers; and (4) water. Final Act. 8. The Examiner finds that the claimed composition is not markedly different from its naturally-occurring counterpart, because there is no indication that purification or recombinant expression of the hLAL has caused the enzyme to have any characteristics that are different from the naturally occurring enzyme(s) isolated from a human source. Id. The Examiner reasons that the addition of the known compounds or the amount of hLAL, such as the protein or polypeptide, does not recite something significantly different than the claimed judicial exception. Id. at 9. The Examiner concludes that, although the claimed composition is not naturally occurring, it does not possess markedly different characteristics from any naturally-occurring counter-part. Therefore, concludes the Examiner, the claimed composition is a product of nature, and is consequently a judicially-created exception to Section 101. Appellant argues first that the Examiner erred in finding that the claimed compositions do not have markedly different characteristics from any natural equivalents, because human serum albumin (“HSA”) markedly changes the properties of the isolated hLAL protein by improving its physical and chemical stability. App. Br. 11. Appellant asserts that the presence of HSA in combination with isolated hLAL in the presently claimed composition provides the isolated hLAL with improved stability, and as such, the composition has the markedly different characteristics from the naturally occurring counterpart of hLAL, such that the claimed Appeal 2019-006072 Application 15/430,815 5 composition does not fall within a judicial exception for patent eligible subject matter. Id. Appellant points to the Examiner’ findings in the rejections of the claims on appeal under 35 U.S.C. § 103, that it was known in the prior art to stabilize enzymes with human serum albumin. App. Br. 9 (citing Adv. Action 5, filed November 21, 2018 (citing Louderback and Xiao)). Appellant contends that the Examiner is therefore taking contradictory positions in the §§ 101 and 103 findings: (1) Appellant has failed to demonstrate that addition of HSA stabilizes hLAL; and (2) that it was well known in the art at the time of Appellant’s filing to stabilize the activity of enzymes, including hLAL, with HSA. Id. Second, Appellant argues that the Examiner erred by impermissibly taking Official Notice. App. Br. 9. Appellant points to the Examiner’s finding that: Stabilization of an enzyme is not equivalent to alteration. When an enzyme is present inside (in vivo) of a cell the cellular mechanism inherently stabilizes the enzyme. When the enzyme is isolated addition of albumin is known to stabilize the enzyme, which does not in any way changes or alters the structure of enzyme. Id. (quoting Adv. Act. 13). Appellant contends that the Examiner’s assertion of these technical facts is not supported by any citation to any reference or work recognized as standard in the pertinent art. Id. (citing In re Ahlert, 424 F.2d 1088, 1091 (C.C.P.A. 1970) (holding that the notice of facts beyond the record taken by the Examiner must be “capable of such instant and unquestionable demonstration as to defy dispute”)). Appeal 2019-006072 Application 15/430,815 6 In performing an analysis of patentability under 35 U.S.C. § 101, we follow the framework set forth by the Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66 (2012). We are also mindful of, and guided by, the United States Patent and Trademark Office’s 2019 Revised Patent Subject Matter Eligibility Guidance, 84(4) Fed. Reg. 50 (January 7, 2019) (the “2019 Guidance”). Appellant’s independent claim 45 recites: “A sterile, aqueous solution consisting of….” Following the first step of the Mayo analysis, we find that the claims are directed to a composition of matter, and therefore fall into one of the broad statutory categories of patent-eligible subject matter under 35 U.S.C. § 101. In the next step of the Mayo analysis, we determine whether the claim at issue is directed to a nonstatutory, patent-ineligible concept, i.e., a law of nature, a phenomenon of nature, or an abstract idea. Mayo, 566 U.S. at 70– 71. If the claim is so directed, we next consider the elements of the claim both individually and “as an ordered combination” to determine whether additional elements “transform the nature of the claim” into a patent-eligible application. Id. at 78–79; see also Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1375 (Fed. Cir. 2015). Specifically, the Supreme Court considered this second step as determining whether the claim recites an element or combination of elements that is “sufficient to ensure that the patent in practice amounts to significantly more than a patent upon the [ineligible concept] itself.” Mayo, 566 U.S. at 72–73. More specifically, in this second step of the Mayo analysis, we look to whether the claim recites one of the judicially-created exceptions to 35 U.S.C. § 101, i.e., an abstract idea, a law of nature, or a natural Appeal 2019-006072 Application 15/430,815 7 phenomenon. See 2019 Guidance 54 (Step 2A, Prong 1). If we determine that the claim recites a judicial exception, we then determine whether the limitations of the claim reciting the judicial exception are integrated into a practical application. Id. (Step 2A, Prong 2). Finally, if we determine that the claim is directed to a judicially- created exception to Section 101, we evaluate the claim under the next step of the Mayo analysis, considering the elements of each claim both individually and “as an ordered combination” to determine whether additional elements “transform the nature of the claim” into a patent-eligible application. Mayo, 566 U.S. at 78–79; see also 2019 Guidance 56 (Step 2B). The claims on appeal recite a composition consisting of: (1) hLAL protein; (2) human serum albumin (“HSA”); (3) one or more buffers; and (4) water. It is undisputed by the parties that the claimed hLAL protein is structurally the same as that occurring naturally. It is also undisputed that human serum albumin is a naturally-occurring product. However, we find that the hLAL enzyme and HSA do not naturally co-exist in an aqueous solution: hLAL is an intracellular enzyme, whereas HSA, as its name implies, is an extracellular protein of the blood serum matrix. See Anderson 22479: Lysosomal acid lipase/cholesteryl ester hydrolase is required for the breakdown of cholesteryl esters and triglycerides that cells acquire from receptor-mediated uptake of low density lipoprotein. The enzyme plays a key intracellular role in supplying cholesterol for cell growth and membrane function and in the regulation of processes that are mediated by cellular cholesterol flux, including internalization of low density lipoprotein and cholesterol biosynthesis and esterification. Appeal 2019-006072 Application 15/430,815 8 (emphasis added, internal citation omitted). Similarly, the claims recite “one or more buffers.” Although buffered solutions certainly occur in vivo, and even intracellularly, the broad language of the limitation accommodates any buffer or buffers within its scope, whether organic or inorganic, and not just those occurring intracellularly. We consequently find that, because the combination of hLAL, HSA, and any possible buffer is not a naturally-occurring combination, we conclude that the claims do not recite a product of nature, and therefore falls outside the scope of the judicial exceptions to Section 101. Consequently, we end our analysis of this issue at this point, and we reverse the Examiner’s rejection of claims 45–47 upon this ground. B. Rejection of clams 45–47 under 35 U.S.C. § 103(a) Issue 1 Appellant argues that the Examiner erred by failing to give any consideration to the amended claim language reciting “consisting of.” App. Br. 7.4 4 Appellant also argues that the claims on appeal should be remanded for further examination, because it is not clear to Appellant whether R. Pariyarath et al., L273S Missense Substitution in Human Lysosomal Acid Lipase Creates a New N‐Glycosylation Site, 397(1) FEBS LETTS. 79–82 (1996) (“Pariyarath”) is used by the Examiner in the Final Office Action as a reference against the claims presently on appeal. App. Br. 6–7. However, the Examiner expressly states in the Final Office Action that “Pariyarath et al. teaches a missence substitution in human lysosomal lipase and the creation of a new N-glycosylation site, with the data confirming an additional N-glycosylation at N271 (Aspargine-271) which Appeal 2019-006072 Application 15/430,815 9 Analysis Appellant notes that the transitional phrase “consisting of” MPEP excludes any ingredient not specified in the claim. App. Br. 7; see also, e.g., Vehicular Techs. Corp. v. Titan Wheel Int’l, Inc., 212 F.3d 1377, 1382–83 (Fed. Cir. 2000). Appellant contends that, despite entering this narrowing amendment of independent claim 45 into the record, the Examiner failed to give any consideration to the newly added limitation “consisting of.” Id. Appellant argues that, because MPEP § 2143.03 states that, to establish a prima facie case of obviousness, the Examiner must give due consideration to all of the limitations of a claim. Id. at 7–8. Appellant contends that, because all of the limitations of claim 45 are not considered in the Advisory Action, the Examiner has committed reversible error, and Appellant argues that prosecution on the merits should be re-opened so that Appellant need not guess as to the actual position for obviousness of the claims that has been taken by the Office. Id. at 8. We agree with Appellant’s understanding of the transitional phrase “consisting of” as a term of art meaning “closing the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith.” See Ex parte Davis and Tuukkanen, 80 U.S.P.Q. 448, 450 (Pat. Office Bd. App. 1948); MPEP 2111.03(II). However, we are capable of interpreting the evidence of record, and the Examiner’s findings meet[s the] vague limitation of claim 30.” Final Act. 7 (emphasis added). It is evident from the Examiner’s finding that Pariyarath is used as a reference only against claim 30, which is not presently on appeal before us. We consequently decline to remand the claims on appeal as requested by Appellant. Appeal 2019-006072 Application 15/430,815 10 and conclusions, in light of this recitation of the claims. We therefore decline to remand the appeal for further examination upon this subject, and we continue on to the merits of Appellant’s argument that the Examiner has failed to establish a prima facie case of obviousness. Issue 2 Appellant argues that the Examiner erred in finding that the cited combined prior art teaches or suggests each and every limitation recited in the claims. App. Br. 8. Analysis The Examiner finds that Anderson teaches molecular cloning of a full length cDNA for human lysosomal acid lipase/cholesteryl ester hydrolase (i.e., hLAL). Final Act. 6. The Examiner finds that Louderback teaches a stable enzyme reference composition having an excellent shelf-life. Final Act. 7. The Examiner finds that the composition of Louderback comprises at least one enzyme of known value; about 20 to about 40 weight percent of at least one alkylene polyol having from 2 to 5 carbon atoms; about 3 to about 8 grams (gm) per deciliter (dl) total protein present in a human serum albumin matrix; and about 60 to about 80 weight percent water. Id. (citing, e.g., Louderback Abstr). However, the Examiner acknowledges that Louderback does not expressly teach that the enzyme in its compositions is hLAL. Id. The Examiner finds that Xiao teaches a composition comprising hLAL that can be used to immunize a mammal, such as a mouse, rat, rabbit, guinea pig, monkey, or human to produce polyclonal antibodies. Final Appeal 2019-006072 Application 15/430,815 11 Act. 7. The Examiner finds that Xiao further teaches that hLAL can be conjugated to a carrier protein, such as bovine serum albumin, thyroglobulin, or keyhole limpet hemocyanin. Id. The Examiner finds that Xiao teaches that, depending on the host species, various adjuvants can be used to increase the immunological response. Id. The Examiner acknowledges that Xiao does not specifically teach using human serum albumin in their composition. Id. (citing Xiao ¶ 166). The Examiner concludes that it would have been prima facie obvious for one of ordinary skill in the art of enzymology to arrive at the claimed composition consisting of a known enzyme, such hLAL, and to stabilize the hLAL solution by the addition of HSA, following the teachings of Louderback or Xiao. Final Act. 7. The Examiner further concludes that it would it would have been obvious to employ normal clinical protocols known in the art to preserve the composition using antioxidants, bacteriostatic agents, preservatives, or stabilizers, and to partition the composition in single or multiple dosage units in sealed containers (vials or ampules), with a reasonable expectation of success. Id. The Examiner reasons that a person of ordinary skill in the art would have been motivated in to combine the references because of the importance of hLAL in atherosclerotic disease. Id. at 7–8. Appellant agrees with the Examiner that Anderson neither teaches nor suggests compositions containing hLAL and HSA. App. Br. 8. Appellant acknowledges the Examiner’s finding that Louderback teaches a composition comprising, inter alia, an enzyme and human serum albumin, but argues that, in so doing, the Examiner has failed to take into consideration the teachings of Louderback as a whole. Id. at 8–9. Appellant Appeal 2019-006072 Application 15/430,815 12 contends that every one of Louderback’s enzyme compositions requires the presence of “about 20 to about 40 weight percent of at least one alkylene polyol having from 2 to 5 carbon atoms,” in addition to human serum albumin. Id. at 9 (citing Louderback Abstr.). Therefore, argues Appellant, taking the teachings of Louderback as a whole, alkylene polyol is a required component, and Appellant further argues that Louderback does not suggest combining any enzyme, much less hLAL protein, with human serum albumin alone. Id. With respect to the teachings of Xiao (which is cited by the Examiner in the alternative with respect to Louderback), Appellant argues that the reference’s only teaching of albumin is that “[i]f desired, a lysosomal acid lipase polypeptide can be conjugated to a carrier protein, such as bovine serum albumin, thyroglobulin, and keyhole limpet hemocyanin.” App. Br. 10 (quoting Xiao ¶ 166). Appellant argues that Xiao is silent with respect to human serum albumin, as recited in the claims on appeal. Id. Appellant also argues that the serum albumin that Xiao teaches is “conjugated to a carrier protein,” i.e., the disclosed bovine serum albumin is covalently bound to the enzyme, not present in a solution as one of several components of a solution, as allegedly recited in independent claim 45. Id. We are not persuaded by the Examiner’s reasoning with respect to the combination of Anderson and Louderback. Example 2 of Louderback, which describes the synthesis of the exemplary embodiments, teaches that: Add albumin (Human Cohn Fraction V) slowly to a 33⅓% by weight aqueous solution of ethylene glycol with continuous mixing. The albumin is preferably dissolved at room temperature, but extended mixing at 2° to 8°C. is acceptable. The amount of albumin added is such that the total protein content is about 4.5±0.5 gm/1. Appeal 2019-006072 Application 15/430,815 13 The pH of the resulting solution is adjusted, if necessary, to 65±0.1 with 6 N HCl or 6 N NaOH. Next, filter the solution through an ethylene glycol impervious filter material having a final filter porosity of 0.4- 0.682. Assay the filtered solution for enzyme activity and salt content to obtain baseline values for each constituent of the composition. Louderback col. 4, ll. 53–68; see also Table III. Louderback thus teaches in this embodiment that a polyol (i.e., ethylene glycol; see col. 3, ll. 13–18) is used in the preparation of the enzyme reference composition, but is removed from the final composition via filtration with an ethylene glycol impervious filter. Id. Appellant’s claim is directed to the composition recited in claim 45, and not to a method of making that composition. Louderback teaches a composition that is made using ethylene glycol, but from which the glycol is removed during the synthetic process, leaving the enzyme and human serum albumin. Summarizing the results, Louderback teaches that: Table XXXII demonstrates that irrespective of pH enzymes tend to exhibit a markedly improved shelf life when stored in the human serum albumin matrix of the instant invention than when stored in the prior art human serum matrix of the composition of Maurukas I and Maurukas II, supra. Id. at col. 19, ll. 53–58. We agree with the Examiner that a person of ordinary skill in the art, comprehending the teachings of Anderson and Louderback, would understand that the addition of human serum albumin wound increase the stability of an enzyme-based composition. Appeal 2019-006072 Application 15/430,815 14 Nevertheless, and as we explained supra, claim 45 recites the claim term “consisting of” which generally excludes the inclusion of additional constituents not directly recited in the claims. Davis, 80 U.S.P.Q. at 450. Loderback expressly teaches that its invention comprises: [A]t least one enzyme of known value; about 20 to about 40 weight percent of at least one alkylene polyol having from 2 to 5 carbon atoms; about 3 to about 8 gm/dl total protein present is a human serum albumin matrix; and about 60 to about 80 weight percent water. Louderback col. 4, ll. 10–15; see also id. at Abstr. Furthermore, Table III of Louderback, upon which the exemplary test embodiments are based, teaches additional constituents. Table III is reproduced below: Table III demonstrates that even if the polyol is filtered out, in addition to the test enzyme, ethylene glycol, and water, these embodiments contain sodium, potassium, calcium, phosphorus, magnesium, chloride, and the protein HBγ-Ag-B. The Examiner has provided no reason as to why a person of ordinary skill in the art would have excluded any of these Appeal 2019-006072 Application 15/430,815 15 additional constituents to arrive at the claimed composition consisting of: (1) hLAL; (2) HSA; (3) a buffer; and (4) water. Furthermore, Table II, and Louderback generally, are silent with respect to buffers, and the Examiner has provided no reasoning as to why a person of ordinary skill in the art would have found it obvious to include a buffer to the combined teachings of Anderson and Louderback. Because the Examiner has provided no reason for why a person of ordinary skill in the art would have found it obvious to exclude these additional elements taught by Louderback, or to include a buffer, we do not sustain the Examiner’s affirmance on this basis. With respect to the combination of Anderson and Xiao, Appellant argues that the teachings of Xiao are irrelevant because Xiao teaches that hLAL is conjugated to the carrier protein (i.e., the BSA). We disagree. Claim 45 recites, in its entirety: “A sterile, aqueous solution consisting of a) human lysosomal acid lipase (hLAL) protein; b) human serum albumin; c) one or more buffers; and d) water.” Claim 45 thus recites no requirement that the enzyme be independent of, or not conjugated to, the HSA, the claim merely requires that the enzyme and the albumin be present in the composition. In other words, a composition that contains hLAL and HSA conjugated to each other, and a composition in which the two elements are not conjugated, both fall within the scope of claim 45. However, we also find that Xiao suffers from infirmities similar to Louderback. Xiao teaches that “[i]f desired, a lysosomal acid lipase polypeptide [such as hLAL] can be conjugated to a carrier protein, such as bovine serum albumin [“BSA”], thyroglobulin, and keyhole limpet hemocyanin.” Xiao ¶ 166. We acknowledge Appellant’s argument that Appeal 2019-006072 Application 15/430,815 16 Xiao does not expressly teach the use of HSA as a carrier protein. In response, the Examiner reasons that substituting BSA for HSA is a simple substitution. See Ans. 23 (citing KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)). However, the Examiner has failed to provide any evidence of record as to why a person of ordinary skill in the art would have found it obvious to substitute BSA for HSA. For example, the Examiner provides no evidence that BSA and HSA would have been known in the contemporaneous art to be equivalent, substitutable carrier protein conjugates in an enzyme-based composition. Furthermore, Xiao teaches additional constituents, including buffers, but also including salts, sugars, excipients, biotinylated hLAL and more. See Xiao ¶¶ 214, 225–230. Again, the Examiner provides no reasoning as to why a person of ordinary skill in the art would have been motivated to exclude these constituents to arrive at the claimed composition consisting of: (1) hLAL; (2) HSA; (3) a buffer; and (4) water. We therefore cannot sustain the Examiner’s prima facie case of obviousness of claims 45–47 over Anderson and Louderback or Xiao, and we consequently reverse the Examiner’s rejection upon this ground. CONCLUSION The Examiner’s rejection of claims 45–47 under 35 U.S.C. § 101 is reversed. The Examiner’s rejection of claims 45–47 under 35 U.S.C. § 103(a) is reversed. REVERSED Appeal 2019-006072 Application 15/430,815 17 Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 45–47 101 Subject Matter Eligibility 45–47 45–47 103(a) Anderson, Louderback Xiao 45–47 Overall Outcome 45–47