Ex Parte Schilling et al

Patent Trial and Appeal BoardMay 12, 2016

12353463 (P.T.A.B. May. 12, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 12/353,463 01114/2009 Stephan Schilling 26263 7590 05/12/2016 DENTONS US LLP P.O. BOX 061080 CHICAGO, IL 60606-1080 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. 2007 5610-0082 2887 EXAMINER WILSON, MICHAEL C ART UNIT PAPER NUMBER 1632 MAILDATE DELIVERY MODE 05/12/2016 PAPER 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. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte STEPHAN SCHILLING, TORS TEN HOFFMANN, and HANS-ULRICH DEMUTH Appeal2014-000705 Application 12/353,463 1 Technology Center 1600 Before ERIC B. GRIMES, FRANCISCO C. PRATS, and RY ANH. FLAX, Administrative Patent Judges. FLAX, Administrative Patent Judge. DECISION ON APPEAL This is a decision on appeal under 35 U.S.C. Â§ 134(a) involving claims directed to a mouse comprising a Qpct gene carrying a knock-out mutation so that the mouse has decreased Qpct activity compared to a wild- type mouse and methods of using such a mouse in disease research. The Examiner rejects claims 1, 7-17, 32, 33, 37, 41-54, and 62-69 under 35 U.S.C. Â§Â§ 101 and 112, first paragraph; claims 46-48 underÂ§ 112, second paragraph; and claims 1, 7-17, 32, and 62----67 underÂ§ 103(a). We have jurisdiction under 35 U.S.C. Â§ 6(b). We reverse. 1 The Real Party in Interest is Probiodrug AG. App. Br. 2. Appeal2014-000705 Application 12/353,463 STATEMENT OF THE CASE Claims 1, 7-17, 32, 33, 37, 41-54, and 62---69 are on appeal and can be found in the Claims Appendix of the Appeal Brief. Claim 1 is the sole independent claim and reads as follows: 1. A mouse comprising mouse cells comprising a glutaminyl peptide cyclotransferase ( Qpct) gene carrying a knock-out mutation; wherein the Qpct gene is a murine Qpct gene; the murine Qpct gene comprises a nucleotide sequence of SEQ ID No. 22; and the mouse has decreased Qpct activity compared to a wild- type mouse. App. Br. 36, Claims Appendix. The following grounds of rejection are on appeal: A. Claims 1, 7-17, 32, 33, 37, 41-54, and 62---69 under 35 U.S.C. Â§ 101 because the claimed invention lacks patentable utility. Final Action 2. B. Claims 1, 7-17, 32, 33, 37, 41-54, and 62---69 under 35 U.S.C. Â§ 112, first paragraph, as not enabled. Final Action 20. C. Claims 46-48 under 35 U.S.C. Â§ 112, second paragraph, as indefinite. Final Action 28. 2 Appeal2014-000705 Application 12/353,463 D. Claims 1, 7-17, 32, and 62----67 under 35 U.S.C. Â§ 103(a) as unpatentable over Lieberman2 or Shi, 3 and Schilling, 4 Ensembl, 5 and Liu. 6 Final Action 28. DISCUSSION A. and B. The rejections of claims 1, 7-17, 32, 33, 37, 41-54, and 62-69 under 35 USCÂ§Â§ 101and112,firstparagraph. The rejections underÂ§Â§ 101 and 112, first paragraph, are largely based on the same allegations and facts and, so, we deal with these issues together. Utility The Examiner determined that the claimed invention lacked patentable utility because there was no link between Qpct and any disease 2 Lieberman et al., Growth Retardation and Cysteine Deficiency in y- glutamyl Transpeptidase-deficient Mice, 93 PROC. NATL. AcAD. SCI. USA 7923-926 (July 1996) (hereinafter "Lieberman"). 3 Shi et al., Disruption of y-Glutamyl Leukotrienase Results in Disruption of Leukotriene D4 Synthesis In Vivo and Attenuation of the Acute Inflammatory Response, 21 MOLECULAR AND CELLULAR BIO. 53 89-395 (Aug. 2001) (hereinafter "Shi"). 4 Schilling et al., Isolation, Catalytic Properties, and Competitive Inhibitors of the Zinc-Dependent Murine Glutaminyl Cyclase, 44 BIOCHEMISTRY 13415--424 (2005) (hereinafter "Schilling"). 5 Ensembl Database No: ENSMUSG00000024084 (available at http://useast.ensembl.org/Mus_musculus/Gene/Summary? db=core ;g= ENSM USG00000024084;r= 17 :79051906-79090243 ;t= ENSMUST00000040789) (hereinafter "Ensembl"). 6 Liu et al., A Highly Efficient Recombineering-Based Method for Generating Conditional Knockout Mutations, 13 GENOME RESEARCH 4 7 6- 484 (2003) (hereinafter "Liu"). 3 Appeal2014-000705 Application 12/353,463 known at the time of filing and it is unclear how a Qpct knock-out mouse could be used in research as a disease model. Final Action 6. The Examiner determined that the Specification lacked description of any phenotype of the Qpct knock-out, failed to teach that the Qpct knock-out mice had any symptoms of any disease and, without such guidance, those of skill could only conduct basic research on the mouse itself. Id. The Federal Circuit has defined the utility requirement as including a substantial utility, such that "an application must show that an invention is useful to the public as disclosed in its current form, not that it may prove useful at some future date after further research." In re Fisher, 421 F.3d 1365, 1371 (Fed. Cir. 2005). An "object of use-testing," that is "objects upon which scientific research could be performed with no assurance that anything useful will be discovered in the end," do not have substantial utility. Id. at 1373. However, a "research tool[], such as a microscope ... [that] has [a] specific benefit ... can offer an immediate, real world benefit" and meets the standard for substantial utility. Id. Also, a specific utility is required, such that "an application must disclose a use which is not so vague as to be meaningless." Id. at 1371. Appellants respond to the Examiner's determinations by pointing out that the Specification identifies how the Qpct gene, Qpct activity, and the resultant formation of pyroglutamic acid(pGlu)-containing AB peptides are linked to several diseases, including Alzheimer's disease, Down Syndrome neurodegeneration, Familial Danish Dementia and Familial British Dementia, inflammatory diseases, schizophrenia, and fertility diseases. App. Br. 12-14 (citing Spec. 30, 37, 38--44). Appellants also point to several 4 Appeal2014-000705 Application 12/353,463 Examples discussed in the Specification relating to gene-dose dependency of Qpct activity, the generation of heterozygous and homozygous Qpct knock- out mice, and a comparison of Qpct activity in the knock-out mice to wild- type mice. App. Br. 14--15. Appellants also identify the von Hoersten Deel. 7 and the Bayer Deel. 8 as evidence of utility and corroboration that the relevant descriptions in the Specification were accurate. App. Br. 11, 15; see also Bayer Deel. i-f 6, Appendix A (indicates that the experiments with 5xFAD-Qpct knock-out mice crossbreeds showed that there is a relationship between Qpct gene activity and characteristic symptoms of Alzheimer's disease). We find Appellants' arguments persuasive. The asserted utility is "specific" because the evidence of record supports Appellants' position that the claimed Qpct knock-out mutation mouse is useful in research on Alzheimer's disease and other diseases related to pGlu-containing peptides. The asserted utility is "substantial" because Alzheimer's disease is a known problem and research into the cause and treatment of the disease are known problems-these define a "real world" context of use. The "specific and substantial utility" is credible because the evidence cited in the Specification and Appellants' briefing is adequate to show that Qpct expression contributes to the symptoms of Alzheimer's and other diseases. See Spec. 1--4, 16-17, 30--44; Bayer Deel.; von Hoersten Deel. 7 Declaration Under 37 C.F.R. Â§ 1.132 by Stephan von Hoersten, filed Sept. 29, 2010 (hereinafter the "von Hoersten Deel."). 8 Declaration Under 37 C.F.R. Â§ 1.132 by Professor Thomas Bayer, filed Sept. 29, 2010 (hereinafter the "Bayer Deel."). 5 Appeal2014-000705 Application 12/353,463 Enablement The Examiner bases the determination that the Specification fails to enable the claimed invention on the asserted lack of utility as set forth above. Final Action 20. We disagree for the reasons set forth above. Further, the Examiner determined that the scope of the claims exceeds the Specification's disclosure. Final Action 21. The Examiner determined that the phenotype of mice with a knock-out of a transferase gene was unpredictable and, so, undue experimentation would have been required to determine the phenotype of the Qpct knock-out mice claimed. Final Action 21. The Examiner determined that claim 1 encompasses any murine species Qpct as a knock-out target and because the Specification does not teach how to make/use a species other than a mouse, undue experimentation would have been required to practice the full scope of the invention. Final Action 21-22. The Examiner determined that the Specification did not teach how to make a viable homozygous knockout mouse and, because disruption of transferase genes is unpredictable and potentially lethal, the Specification did not provide adequate guidance for homozygous mice with a disruption in a Qpct gene. Final Action 22. Finally, the Examiner determined that the Specification did not teach making constitutive knockout mice (per claim 10), conditional knockout mice (per claim 11 ), or linking the Qpct gene to a tissue specific promoter (per claim 16). Final Action 23. Appellants argue that the Examiner's determinations regarding the claimed knock-out mouse's phenotype and art unpredictability are unfounded because the survivability/viability of Qpct knock-out mice was shown and the respective phenotype of reduced/eliminated Qpct activity was 6 Appeal2014-000705 Application 12/353,463 demonstrated in heterozygous and homozygous Qpct knock-out mice as compared to wild-type. App. Br. 18-20 (discussing, inter alia, Example 15 in Spec.). We find Appellants' argument persuasive on this point. Appellants point out that the recited sequence SEQ ID No. 22 of claim 1 is from the species Mus musculus, the house mouse. App. Br. 18; see also Spec. 51 and Ensembl (identifying the gene sequence as being of a house mouse). The claims are directed to a mouse carrying a Qpct knock-out mutation, the recited Qpct gene is of a house mouse, and the recited knock- out mouse has decreased Qpct activity compared to a wild-type mouse. See App. Br. 36, Claim Appendix (claim 1). We find Appellants' argument persuasive on this point. Appellants argue that the Specification described breeding heterozygous transgenic mice and crossing them to produce homozygous mice and also cross breeding homozygous mice, generally, and also working examples of homozygous Qpct knock-out mice reduced to practice. App. Br. 20-21 (citing Spec. 23, 11. 15-25 and Examples 1-14 ). Appellants argue that the Specification provided evidence that the Qpct knock-out was not lethal. App. Br. 21 (citing Spec. 90, 11. 8-15, Example 15 (which describes producing heterozygous and homozygous Qpct knock-out mice, further breeding these animals for human disease studies, and evidence that the pharmacological inhibition of Qpct does not have obvious deleterious side effects)). Appellants also point to the Bayer Declaration as evidence that the procedures disclosed in the Specification for producing homozygous Qpct knock-out animals were conventional and would be expected to succeed. App. Br. 21. We find Appellants' arguments persuasive on this point. 7 Appeal2014-000705 Application 12/353,463 Appellants argue that the Specification at, inter alia, pages 5, 8, 9, 50, 57, 77-80, and 86-90 (various working examples), and Figs. 1 and 20, describes viable constitutive Qpct knock-out mice and how to produce them. App. Br. 22-23. Appellants also produced evidence, by way of the Bayer Deel. i-fi-14--8, that the Qpct knock-out per the Specification's disclosure was not lethal. Appellants argue that the Specification at, inter alia, pages 5, 10, 51, 52, 57, 81-83, 85, 86, 88, and Figs. 1and26 describes (various working examples) producing and breeding viable conditional Qpct knock-out mice. App. Br. 23-24. Finally, Appellants argue that the Specification describes "extensive guidance" on using tissue specific promoters in the Qpct knock- out mouse at pages 20 and 24. App. Br. 24--25. The Specification describes several examples of "suitable tissue-specific promoters" that could be used to "affect tissue specific expression" in the Qpct knock out mouse. Spec. 24, 11. 4--1 7. Appellants argue that the high level of skill in the art and the guidance in the Specification enable an ordinary skilled artisan to make a Qpct knock-out gene carrying a mutation operably linked to a tissue specific promoter. We find Appellants' arguments persuasive on these points. For these reasons, the rejections of claims 1, 7-17, 32, 33, 37, 41-54, and 62---69 under 35 U.S.C. Â§Â§ 101 and 112, first paragraph, are reversed. 8 Appeal2014-000705 Application 12/353,463 C. The rejection of claims 46-48 under 35 US.C. Â§ 112, second paragraph, as indefinite. The Examiner determined that claims 46-48 are indefinite because the metes and bounds of"lowering of the [pGlu3JAB2-30/31/32 [sic] or [pGlu11 JAB11-40/42/43," and "[pGlu3JAB3-40 peptides" and "[pGlu3JAB3- 42 peptides" cannot be determined from the teachings in the Specification. Final Action 28. Appellants point out that the Specification discusses the formation and prevalence of pGlu-AB peptides in plaque deposits of patients suffering Alzheimer's disease and that, specifically, [pGlu3JAB3-40/42/43 peptides and [pGlu11 JAB11-40/42/43 peptides are associated with Alzheimer's disease and other diseases. App. Br. 27 (discussing Spec. 30-33, 35, 38- 41 ). Further, the Specification describes "AB concentrations can be analyzed using an ELISA quantifying total AB(x-42) or AB(x-40) as well as [pGlu3JAB3-40/42/43 or [pGlu11 JAB11-40/42/43" and that an ELISA kit to quantify [pGlu3JAB3-42 was commercially available and an ELISA to quantify [pGlu3JAB3-40 was described in the prior art. Spec. 35, 11. 5-17. The Specification states that "AB is generated by proteolytic processing of the B-amyloid precursor protein (APP) ... , which is sequentially cleaved by B-secretase at the N-terminus and by y-secretase at the C-terminus of AB. . . . In addition to the dominant AB peptides starting with L-Asp at the N-terminus (ABl-42/40), a great heterogeneity ofN- terminally truncated forms occurs in senile plaques." Spec. 2:37-3 :5. The Specification also states that "[a]dditional post-translational processes may further modify the N-terminus by isomerization or 9 Appeal2014-000705 Application 12/353,463 racemization of the aspartate at position 1 and 7 and by cyclization of glutamate at residues 3 and 11. Pyroglutamate-containing isoforms at position 3 [pGlu3 AB3-40/42] represent the prominent forms -approximately 50 % of the total AB amount - of the N-truncated species in senile plaques." Id. at 3: 13-17. We find the Appellants' argument persuasive on this issue. In view of the Specification's description ofN- and C-terminally truncated forms of AB and cyclization of glutamate (to form pGlu) at positions 3 and 11, it is not clear what the Examiner specifically finds indefinite about the claim language or why the metes and bounds of the claim language cannot be determined in view of the Specification. For these reasons, the rejection of claims 46-48 under 35 U.S.C. Â§ 112, second paragraph, is reversed. D. The rejection of claims 1, 7-17, 32, and 62-67 under 35 USC Â§ 103(a) as unpatentable over Lieberman or Shi, and Schilling, Ensembl, and Liu. The Examiner determined that Lieberman and/or Shi taught generating knock-out mice (heterozygous, homozygous, and constitutive), focusing on genes for transferase enzymes, but not the Qpct gene. Final Action 29. The Examiner determined that Schilling taught the Qpct gene and cDNA and that Ensembl "appears to be the sequence disclosed by Schilling and appears to encompass SEQ ID NO: 22." Id. The Examiner determined that it would have been obvious to substitute the Qpct gene disclosed by Schilling for the genes constitutively 10 Appeal2014-000705 Application 12/353,463 knocked-out as described by Lieberman and/or Shi. Id. The Examiner determined that Liu supports the desire to knock-out any gene in mouse ES cells using conditional knock-outs, as conditional knock-out vectors were well known. Id. The Examiner determined that there was motivation to combine these references because transferases have functional and structural similarities and it was well known to make mice with a disruption in any transferase gene to study its function in vivo. Final Action 29--30. As support for this position, the Examiner identified the Wong, 9 Schulz, 10 Domino, 11 Engle, 12 and Ellies 13 references that disclose disrupting transferase genes for studying their functions in vivo. Ans. 39--40. Appellants argue, among other things, that the Examiner has not provided sufficient rationale to modify the cited references to reach the 9 Wong et al., Disruption of the Type III Adenylyl Cyclase Gene Leads to Peripheral and Behavioral Anosmia in Transgenic Mice, 27 NEURON 487- 497 (Sept. 2000) (hereinafter "Wong"). 10 Schulz et al., Disruption of the Guanylyl Cyclase-C Gene Leads to a Paradoxical Phenotype of Viable but Heat-stable Enterotoxin-resistant Mice, 100 J. CLIN. INVEST. 1590-1595 (Sept. 1997) (hereinafter "Schulz"). 11 Domino et al., Deficiency of Reproductive Tract a(l,2)Fucosylated Glycans and Normal Fertility in Mice with Targeted Deletions of the FUTJ or FUT2 a(l,2)Fucosyltransferase Locus, 21 MOLECULAR AND CELLULAR BIO. 8336-8345 (Dec. 2001) (hereinafter "Domino"). 12 Engle et al., Physiological Role of mGSTA4-4, a Glutathione S-transferase Metabolizing 4-hydroxynonenal: Generation and Analysis of mGsta4 Null Mouse, 194 TOXICOLOGY AND APPLIED PHARMACOLOGY 296-308 (2004) (hereinafter "Engle"). 13 Ellies et al., Core 2 Oligosaccharide Biosynthesis Distinguishes Between Selectin Ligands Essential for Leukocyte Homing and Inflammation, 9 IMMUNITY 8 81-890 ( 1998) (hereinafter "Ellies"). 11 Appeal2014-000705 Application 12/353,463 claimed Qpct knock-out mouse. App. Br. 32. We find this argument persuasive. Missing from the Examiner's explanation of the prima facie case for obviousness is "some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness." KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007) (quoting In re Kahn, 441F.3d977, 988 (Fed. Cir. 2006). An invention "composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art .... [I]t can be important to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does." Id. Here, the Examiner provides no practical reason for making the combination other than a skilled artisan might want to and would be able to do so, without indicating why they would be motivated to investigate the Qpct gene for any reason other than scientific curiosity. Cf In re Stemniski, 444 F .2d 5 81, 5 86 ( CCP A 1971) ("[W]hat on this record-other than abstract, theoretical or academic considerations-would lead one of ordinary skill ... to obtain the claimed compounds? Certainly no practical considerations which promote the progress of useful arts or are of use to society are manifest."). For these reasons, the rejection of claims 1, 7-17, 32, and 62----67 under 35 U.S.C. Â§ 103(a) is reversed. 12 Appeal2014-000705 Application 12/353,463 SUMMARY The rejections of claims 1, 7-17, 32, 33, 37, 41-54, and 62---69 under 35 U.S.C. Â§Â§ 101 and 112, first paragraph, are reversed. The rejection of claims 46-48 under 35 U.S.C. Â§ 112, second paragraph, is reversed. The rejection of claims 1, 7-17, 32, and 62---67 under 35 U.S.C. Â§ 103(a) is reversed. REVERSED 13