Case Western Reserve University

Patent Trials and Appeals Board

Mar 24, 2022

2020004239 (P.T.A.B. Mar. 24, 2022)

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. 14/600,564 01/20/2015 Ram Nagaraj CWR-021503US CIP 5155 68705 7590 03/24/2022 TAROLLI, SUNDHEIM, COVELL & TUMMINO, LLP 1300 EAST NINTH STREET SUITE 1700 CLEVELAND, OH 44114 EXAMINER FONTAINHAS, AURORA M ART UNIT PAPER NUMBER 1649 NOTIFICATION DATE DELIVERY MODE 03/24/2022 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): docketing@tarolli.com rkline@tarolli.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte RAM NAGARAJ and ROOBAN B. NAHOMI Appeal 2020-004239 Application 14/600,564 Technology Center 1600 BEFORE RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and JOHN E. SCHNEIDER, Administrative Patent Judges. SCHNEIDER, Administrative Patent Judge. DECISION ON APPEAL STATEMENT OF THE CASE Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims 12, 18, and 19.2 We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42(a). Appellant identifies the real party in interest as Case Western Reserve University. Appeal Br. 2. 2 Claims 13, 15, and 20-24 are pending in the application but have been withdrawn from consideration. Final Act. 2. Appeal 2020-004239 Application 14/600,564 2 CLAIMED SUBJECT MATTER The claims are directed to the use of acetylated crystallin polypeptides as therapeutic agents. Claim 12, reproduced below, is illustrative of the claimed subject matter: Claim 12: A method of inhibiting apoptosis of lens epithelial cells associated with or resulting from cataract formation in a subject, the method comprising: administering to the cell an amount of a therapeutic polypeptide effective to inhibit pathological apoptosis of the cell, wherein the therapeutic polypeptide has the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4. REFERENCES The prior art relied upon by the Examiner is: Name Reference Date Steinman et al. US 2013/0071392 A1 Mar. 21, 2013 Ying-Wei Mao et al., Human bcl-2 Gene Attenuates the Ability of Rabbit Lens Epithelial Cell against H2O2-induced Apoptosis through Down- regulation of the αB-crystallin Gene, J. Biological Chem. Vol. 276, No. 46, pp 43435-45 (2001) Karin Sadoul et al., The Tale of Protein Lysine Acetylation in the Cytoplasm, J. Biomed. Biotech. Vol. 2011, Article ID 970382 (2011) REJECTION Claims 12, 18, and 19 have been rejected under 35 U.S.C. § 103(a) as unpatentable over Mao in view of Steinman and Sadoul. OPINION The issue before us is whether a preponderance of the evidence supports the Examiner’s conclusion that the subject matter of claims 12, 18, and 19 would have been obvious to one skilled in the art at the time the invention was made over Mao combined with Steinman and Sadoul. Appeal 2020-004239 Application 14/600,564 3 The Examiner finds Mao teaches oxidative stress-induced apoptosis is linked to cataractogenesis. Final Act. 3. The Examiner finds αB-crystallin prevents apoptosis from a variety of stress conditions including UVA radiation. Id. at 4. The Examiner finds Steinman teaches αB-crystallin protects lens epithelial cells from different forms of stress including oxidative stress. Id. The Examiner finds Steinman teaches the administration of proteins or peptides including peptides that are nearly identical to SEQ ID NO: 3 and SEQ ID NO:4 of the present claims with the differences being an additional amino acid in SEQ ID NO:4. Id.The Examiner finds that Steinman teaches the peptides can be modified including acetylated and that the peptides have the same therapeutic activity as the intact protein. Id. The Examiner finds Sadoul teaches acetylation of lysine in posttranslational proteins. Id. at 5. The Examiner finds Sadoul teaches αB- crystallin acetylated at lysine 92 and that crystallins are chaperones whose activity is regulated by acetylation. Id. The Examiner concludes: It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosure of Mao, Steinman and Sadoul. The person of ordinary skill in the art would have been motivated to make and use the invention as claimed because Mao teaches that αB- crystallin plays a role in preventing apoptosis due to oxidative stress in lens epithelial cells and Steinman teaches that crystalline proteins are involved in preventing apoptosis in oxidative stress (see paragraph 45). Therefore, one of ordinary skill would be motivated to administer the proteins taught by Steinmann since they are easier to administer than the gene therapy taught by Mao. Further, Steinman teaches the instantly claimed SEQ ID NO: 4 except the missing Val amino acid, as Appeal 2020-004239 Application 14/600,564 4 their SEQ ID NO: 2. One of ordinary skill in the art would be able to produce the instantly claimed sequences with the appropriate acetylation since Steinman teaches acetylation and modification of these peptides while the peptide is up to 25 amino acids in length but not more (see paragraphs 12, 58, 110 and claims 1, 6, 7, 9 and 10) and Sadoul teaches that the lysine at position 92 of αB-crystallin and position of 70 of αA- crystallin are acetylated and that these regions are linked to their activity (see page 8, 1st column, 1st paragraph). The lysine in the 92 position of αB-crystallin is the 20th amino acid in both instant SEQ ID NO: 4 and Steinman SEQ ID NO: 2. Therefore, one would be motivated to specifically acetylate these lysine positions in SEQ ID NOs: 3 and 4 to improve their activity. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references. Therefore, claims 12, 18 and 19 are obvious over Mao, Steinman and Sadoul. Id. at 5-6. Appellant contend Mao does not teach or suggest inhibiting apoptosis by administering a therapeutic peptide wherein the peptide has the amino acid sequence SEQ ID NO: 3 or SEQ IDNO: 4. Appeal Br. 5. Appellant contends Mao does not teach or suggest the peptide be acetylated or that acetylation has any therapeutic effect. Id. Appellant contends Steinman does not teach of suggest inhibiting apoptosis associated with or resulting from cataract formation by administering an effective amount of a polypeptide. Id. at 5-6. Appellant contends Steinman does not teach or suggest the claimed peptide sequences wherein the peptide SEQ ID NO: 3 is acetylated at lysine 70 of αA-crystallin or where peptide SEQ ID NO:4 is acetylated at lysine 96 of αB-crystallin. Id. Appellant contends while Steinman teaches that the peptide can be modified including by acetylation, Appeal 2020-004239 Application 14/600,564 5 Steinman '392 provides no indication that any of the residues of a full-length αA-crystallin or αB-crystallin peptide are specifically modified, let alone that any of the specific acetylated residues of the therapeutic peptide fragments having SEQ ID NO: 3 and SEQ ID NO: 4 have been modified through acetylation, nor the effect of such acetylation. Notably, Steinman '392 provides no teaching or suggestion that acetylation of any peptide residue would inhibit pathological protein aggregation and/or pathological apoptosis in lens epithelial cells. Id. at 7. Appellant contends Sadoul does not correct the deficiencies of Mao and Steinman. Id. at 8. Appellant contends Sadoul only teaches full length αA-crystallin and αB-crystallin sequences where the lysines have been acetylated. Id. Appellant contends Sadoul does not teach or suggest any therapeutic segments of the proteins or how the protein regulate apoptotic activity. Id. Appellant also contend Sadoul teaches that it is deacetylation that activates the protein and not acetylation. Id. at 8-9. Appellant contends As there was no teaching in the prior art that that peptide fragments of α-crystallins having the amino acid sequences SEQ ID NO: 3 or 4 could inhibit pathological apoptosis of lens epithelial cells when administered to the cells, one skilled in the art would not have had a reasonable expectation of success in view of Mao, Steinman '392 and Sadoul that the peptide fragments having an amino acid sequences SEQ ID NO: 3 or 4 are indeed effective for inhibiting apoptosis of lens epithelial cells associated with or resulting from cataract formation in a subject. Id. at 11. Appeal 2020-004239 Application 14/600,564 6 Appellant contends the art taught that the effect of αA crystallin is unpredictable. Id. at 12. In support of this contention Appellant cites to Lin3 which teaches while acetylation of the crystallin protein appeared to have an anti-cataract effect, the acetylation was believed to have occurred at cysteinyl residues not at lysine. Id. at 12-13, citing Lin, 1453. Appellant contends that one skilled in the art, reading Sadoul and Lin would find that the effect of acetylation of crystallins was unpredictable and that acetylation may actually impede chaperone function and contribute to lens opacity. Id. at 13. Finally, Appellant contends the claims are patentable as there is sufficient evidence of unexpected results to overcome the Examiner’s prima facie case of obviousness. Id. at 14. Appellant points to the Specification where it reports that acetylated proteins and peptides showed a 10 to 40% increase in chaperone activity as compared with unacetylated proteins and peptides. Id. We adopt the Examiner’s findings of fact, reasoning on scope and content of the prior art, and conclusions set out in the Final Action and Answer regarding this rejection. We find the Examiner has established a prima facie showing that the subject matter of the claims would have been obvious over Mao combined with Steinman and Sadoul to a person of ordinary skill in the art at the time the invention was made. Appellant has not produced persuasive evidence showing, or persuasively argued, that the Examiner’s determinations on obviousness are incorrect. Only those arguments made by Appellant in the Briefs have been considered in this 3 Peiping P. Lin et al., In vivo acetylation identified at lysine 70 of human lens αA-crystallin, 7 Protein Sci. 1451 (1998). Appeal 2020-004239 Application 14/600,564 7 Decision. Arguments not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2015). We have identified claim 12 as representative; therefore, all claims stand or fall with claim 12. We address Appellant’s arguments below. Appellant argues that each of the references fails to teach one or more of the limitations of the claims. For example, Appellant argues “Mao does not teach or suggest a therapeutic peptide having the specific amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4, let alone a peptide that is acetylated at lysine 70 of αA-crystallin or at lysine 92 of αB-crystallin. In fact, Mao fails to teach or recognize that acetylation at these positions contributes to any therapeutic effect.” Appeal Br. 5. While this point may be true, these limitations are taught by Steinman and Sadoul. See Steinman ¶¶ 45, 46, 110; Sadoul, 8. “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references. . . . [The reference] must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Appellant also contend that Steinman only gives general guidance regarding possible peptide modifications and does not teach or suggest the specific modifications made in the peptides recited in claim 12. Appeal Br. 6-7. This argument is not persuasive. While Steinman only contains a general teaching of modifications that can be made to the peptides taught in Steinman, Sadoul teaches acetylation at the specific amino acids and that acetylation at those sites positively affects the activity of the crystallins. Sadoul, 8. Appeal 2020-004239 Application 14/600,564 8 Appellant contends Sadoul does not teach or suggest any therapeutically relevant fragments of full length a-crystallin, let alone the specific therapeutic polypeptide fragments having the amino acid sequence SEQ ID NO: 3 acetylated at lysine 70 of αA-crystallin or SEQ ID NO: 4 acetylated at lysine 92 of αB-crystallin as claimed. Moreover, Sadoul provides no discussion regarding how the apoptotic activity α-crystallin is regulated by acetylation in lens epithelial cells. Again, while this may be true, the teachings missing from Sadoul are found in Mao and Steinman. See Ans. 8. Appellant contends Steinman does not teach or suggest the specific acetylated peptides recited in claim 12. Appeal Br. 7. Again, while this may be true, as the Examiner points out, Steinman teaches the same sequences as recited in the claims with the exception of the acetylated lysines and a C- terminal amino acid in SEQ ID NO:4. Ans. 8. However, Sadoul teaches that αA-crystallin, a chaperone protein, is acetylated on lysine 70, a region that is important for its activity; αB-crystallin is acetylated on lysine 92. Sadoul, 8. Appellant contends that one skilled in the art would not have had a reasonable expectation of success. Appeal Br. 11. Appellant supports this contention by pointing out that the activity of some chaperones is improved by deacetylation and not acetylation. Id. at 12. Appellant also cites to Lin which Appellant contends would lead one skilled in the art to believe that one could not predict what effect post-translational acetylation would have on a peptide. Id. at 13. We have considered Appellant’s argument and are not persuaded. While Sadoul teaches that a chaperone can be activated by deactylation, Sadoul does not teach that crystallins are activated by deacetylation. Sadoul, 8. Rather, Sadoul suggests the opposite. Id. Appeal 2020-004239 Application 14/600,564 9 With respect to Lin, we agree with the Examiner that the art has evolved since the 1998 reference as evidenced by the prior art references of record, Mao, Steinman and Sadoul, which teach that there are known modifications to the proteins that affect its activity status and that the specific size of the peptides, as taught by Steinman, are stable and effective in treatment. Therefore, the combination of the references provides sufficient and specific guidance to allow the skilled artisan to determine the appropriate peptide size and modifications in order to produce an effective and stable peptide for treatment. Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. "Good science and useful contributions do not necessarily result in patentability." PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007). Ans. 11-12. Turning to the issue of unexpected results, Appellant has not provided any persuasive evidence, other than attorney argument, that the results are unexpected. See Appeal Br. 16. “[I]t is well settled that unexpected results must be established by factual evidence. ‘Mere argument or conclusory statements in the specification does not suffice.’” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997) (quoting In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984)). “Attorneys’ argument is no substitute for evidence.” Johnston v. IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989). Moreover, as the Examiner points out, the results reported in the Specification would, have been expected given the teachings of the prior art. Ans. 12. There is no unexpected result since the prior art already taught that the individual modifications had similar effects and one Appeal 2020-004239 Application 14/600,564 10 would expect that these modifications would produce a better activity, as shown by Sadoul. Sadoul teaches that protein chaperons such as Hsp90 can be acetylated on several lysine residues and its activation state depends on its acetylation status (see page 7, 2nd column, 3rd paragraph). Id. Based on the foregoing we conclude that a preponderance of the evidence supports the Examiner’s conclusion that the subject matter of claims 12, 18, and 19 would have been obvious to one skilled in the art at the time the invention was made over Mao combined with Steinman and Sadoul. CONCLUSION The Examiner’s rejection is affirmed. More specifically, The rejection of claims 12, 18, and 19 under 35 U.S.C. § 103(a) as unpatentable over Mao in view of Steinman and Sadoul is affirmed. DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 12, 18, 19 103(a) Mao, Steinman, Sadoul 12, 18, 19 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED