Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 6, 2026 has been entered. No claim amendments were submitted with this reply.
Claims 24-29 and 31-33 are pending in the application and examination before the Office.
The rejections of record can be found in the previous Office action, dated October 7, 2025.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 6, 2026 was filed after the mailing date of the first Office action on the merits on June 18, 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 24-29, 31, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Schon (Eur. J. Pharm. Biopharm., September 2015, 95(Pt. B):343-352, cited in IDS) in view of De Faria (Invest Ophthalmol Vis Sci. 2016 Aug 1;57(10):4356-66), Di Rosa (Curr Neuropharmacol. 2016;14(8):810-825), and Ghosh (Invest. Ophthalmol. Vis. Sciences, March 20, 2018, 59(4):AMD104-AMD1 13, cited in IDS).
Schon teaches that viral vectors, such as AAV, may be administered to a patient's retinal pigment epithelial (RPE) cells by subretinal injection (page 334, right column, sixth paragraph), which is pertinent to claims 24, 29, and 31. Schon also teaches that this method is useful for delivering a therapeutic gene to the retina (page 343, right column).
Schon further teaches that AAV8 is especially useful for transducing RPE cells and photoreceptors (page 334, right column, last paragraph), which is pertinent to claims and 26-28.
Schon further teaches the use of VMD2 promoter (i.e., hVMD2) for delivery to RPE cells (page 334, right column, first paragraph), which is pertinent to claim 25.
Schon further teaches that this method is useful to treat diabetic retinopathy (page 347, right column, second paragraph).
Schon further teaches that the patient may be human (page 347, left column, first paragraph), which is pertinent to claim 33.
However, Schon does not teach beta A1-crystallin.
De Faria teaches that lysosomal impairment and autophagic dysfunction are early events present in the pathogenesis of diabetic retinopathy, and are possible targets for developing a novel therapeutic strategy to treat diabetic retinopathy (abstract).
Di Rosa teaches that treatments which promote autophagy may be useful in preventing death of retinal cells in diabetic retinopathy (page 818, right column, second paragraph).
Di Rosa also teaches that autophagy involves trafficking proteins to the lysosome for degradation (page 810, left column, first paragraph).
Ghosh teaches that beta A1-crystallin influences the clearance functions of lysosomes such as phagocytosis and autophagy, and deficiency of beta A1-crystallin results in compromised lysosome-mediated clearance in retinal pigment epithelial (RPE) cells (page AMD 104, also see page AMD109, left column).
Ghosh also teaches that beta A1-crystallin is useful in treating conditions of the eye where lysosomal dysfunction is relevant (abstract and page AMD112, left column, first paragraph).
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of Schon, De Faria, Di Rosa, and Ghosh to arrive at the claimed invention. The use of AAV vectors as a method to treat diabetic retinopathy was known in the art, according to Schon. De Faria teaches that patients with diabetic retinopathy have impaired lysosomal function and autophagic dysfunction, and both De Faria and Di Rosa teach that addressing these problems may be useful in treating diabetic retinopathy. A possible solution to this known problem in the art is taught by Ghosh, as Ghosh teaches that beta A1-crystallin is necessary for proper function of the lysosome and autophagy. Ghosh also teaches that administration of beta A1-crystallin is useful in treating conditions where lysosomal dysfunction is relevant. The use of beta A1-crystallin according to Ghosh in the method of Schon would therefore predictably solve the known problem in the art taught by De Faria and Di Rosa. One of ordinary skill could apply this known solution to the known problem by known methods, with each component of the combination performing its known, usual function to affect a predictable result.
Applicant argues that the cited references do not provide a person having ordinary skill in the art with a reasonable expectation of success in performing the claimed method to treat diabetic retinopathy, and that the results from performing the claimed method are unexpected. Applicant relies upon a declaration under 37 CFR 1.132 from Dr. Debasish Sinha ("the Sinha Declaration") in making these arguments.
Applicant's arguments have been considered fully but are not found to be persuasive.
When an applicant timely submits evidence traversing a rejection, the examiner must reconsider the patentability of the claimed invention. The ultimate determination of patentability must be based on consideration of the entire record, by a preponderance of evidence, with due consideration to the persuasiveness of any arguments and any secondary evidence. In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). The submission of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. In re Chupp, 816 F.2d 643, 2 USPQ2d 1437 (Fed. Cir. 1987). Facts established by rebuttal evidence must be evaluated along with the facts on which the conclusion of a prima facie case was reached, not against the conclusion itself. In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990). MPEP 716.01(d).
First, the Sinha Declaration at paragraphs 8-12 describes the differences between the cited references, and notes that Schon, De Faria, and Di Rosa do not teach beta A1-crystallin. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). MPEP 2145(IV).
Schon teaches that AAV delivery of a therapeutic gene is useful in treating diabetic retinopathy (page 347: "4.3. Gene therapies of retinal disorders with unclear genetic etiology").
De Faria teaches that lysosomal impairment and autophagic dysfunction are early events present in the pathogenesis of diabetic retinopathy, and are possible targets for developing a novel therapeutic strategy to treat diabetic retinopathy (abstract).
Ghosh teaches that beta A1 crystallin is useful in treating conditions of the eye where lysosomal dysfunction is relevant. (page AMD112, left column, first paragraph: "...our data indicated that beta A3/A1 crystallin is an attractive target for rejuvenation of lysosomal function...").
The use of beta A1-crystallin according to Ghosh in the method of AAV treatment taught by Schon would therefore predictably solve the known problem in the art taught by De Faria and Di Rosa.
Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring 'absolute predictability of success.'"). Obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). MPEP 2143.02.
The Sinha Declaration attempts to make a legal conclusion as to the obviousness rejection, which is not entitled to any weight. In re Chilowsky, 306 F.2d 908, 134 USPQ 515 (CCPA 1962). In re Lindell, 385 F.2d 453, 155 USPQ 521 (CCPA 1967). Although an affidavit or declaration which states only conclusions may have some probative value, such an affidavit or declaration may have little weight when considered in light of all the evidence of record in the application. In re Brandstadter, 484 F.2d 1395, 179 USPQ 286 (CCPA 1973). MPEP 716.01(c).
With regards to Applicant's assertion of unexpected results in paragraph 13 of the Sinha Declaration, Di Rosa teaches that treatments which promote autophagy may be useful in preventing death of retinal cells in diabetic retinopathy, for reasons described above. It appears that the proposed treatment is performing nothing more than its expected function.
"Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). MPEP 716.02(c)(II).
When weighing the teachings of the cited reference against the Sinha Declaration, the preponderance of the evidence suggests that the results are not unexpected. In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977).
This rejection is therefore maintained.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Li (US20180360930A1) in view of De Faria (Invest Ophthalmol Vis Sci. 2016 Aug 1;57(10):4356-66), Di Rosa (Curr Neuropharmacol. 2016;14(8):810-825), and Ghosh (Invest. Ophthalmol. Vis. Sciences, March 20, 2018, 59(4):AMD104-AMD1 13, cited in IDS).
Li teaches that therapeutic proteins can by administered to a patient for the treatment of diabetic retinopathy (para. 0008-0009 and 0041).
However, Li does not teach beta A1-crystallin.
De Faria teaches that lysosomal impairment and autophagic dysfunction are early events present in the pathogenesis of diabetic retinopathy, and are possible targets for developing a novel therapeutic strategy to treat diabetic retinopathy (abstract).
Di Rosa teaches that treatments which promote autophagy may be useful in preventing death of retinal cells in diabetic retinopathy (page 818, right column, second paragraph).
Di Rosa also teaches that autophagy involves trafficking proteins to the lysosome for degradation (page 810, left column, first paragraph).
Ghosh teaches that beta A1-crystallin influences the clearance functions of lysosomes such as phagocytosis and autophagy, and deficiency of beta A1-crystallin results in compromised lysosome mediated clearance in retinal pigment epithelial (RPE) cells (page AMD 104, also see page AMD109, left column).
Ghosh also teaches that beta A1-crystallin is useful in treating conditions of the eye where lysosomal dysfunction is relevant (abstract and page AMD112, left column, first paragraph).
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of Li, De Faria, Di Rosa, and Ghosh to arrive at the claimed invention. The use of subretinal injection of therapeutic protein as a method to treat diabetic retinopathy was known in the art, according to Li. De Faria teaches that patients with diabetic retinopathy have impaired lysosomal function and autophagic dysfunction, and both De Faria and Di Rosa teach that addressing these problems may be useful in treating diabetic retinopathy. A possible solution to this known problem in the art is taught by Ghosh, as Ghosh teaches that A1-crystallin is necessary for proper function of the lysosome and autophagy. Ghosh also teaches that administration of beta A1-crystallin is useful in treating conditions where lysosomal dysfunction is relevant. The use of beta A1-crystallin according to Ghosh in the method of Li would therefore predictably solve the known problem in the art taught by De Faria and Di Rosa. One of ordinary skill could apply this known solution to the known problem by known methods, with each component of the combination performing its known, usual function to affect a predictable result.
Applicant argues that Li does not remedy the alleged deficiencies of De Faria, Di Rosa, and Ghosh. This is not found persuasive, for reasons described supra.
This rejection is therefore maintained.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Zigler (Prog Retin Eye Res. 2014 Nov 13;0:62–85) teaches that mutant mice deficient in beta A1-crystallin have abnormal vascularity in the retina (Figure 9H and 9I: "...while the Nuc1 vascular pattern is sparse, appears to be lacking a deep capillary plexus and has an abnormal pattern..."). Zigler also teaches that over-expression of bA3/A1-crystallin is capable of rescue of V-ATPase activity in the above mutant mice (Figure 13). Zigler also teaches that beta A1-crystallin is expressed in retinal pigment epithelial (RPE) cells, and are required for proper function of lysosomes (abstract and Figures 13 and 14, also page 76: "This suggests that beta A3/A1 crystallin has an important function in the lysosomes of the RPE cell.").
Kim (Diabetologia. 2012 Oct;55(10):2835-2844) teaches that a recombinant adenovirus expressing alpha-A-crystallin is useful in treating diabetic retinopathy (abstract and Figure 5).
No claim is allowed.
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/PETER JOHANSEN/Examiner, Art Unit 1644
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