DETAILED ACTION
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 .
Status of Application/Amendment/Claims
This Office action is in response to the communications filed on August 27, 2026.
Currently, claims 1, 3-8, 12-13, 15-16, and 18-25 are pending in the instant application. Claims 6-8 are withdrawn from further consideration as being drawn to nonelected inventions, there being no allowable generic or linking claim. Accordingly, claims 1, 3-5, 12-13, 15-16, and 18-25 are under examination on the merits in the instant application.
The following rejections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections/objections not repeated in this Office action are hereby withdrawn.
Drawings
The petition to accept color drawings filed on August 27, 2026 is acknowledged. A decision on the petition has not been rendered and will be separately mailed from this Office action.
Maintained Rejections
Claim Rejections - 35 USC § 103
Claims 1 and 3-5 remain rejected under 35 U.S.C. 103 as being unpatentable over Schwartz et al. in view of Moiseyev et al. and Blanks et al. for the reasons as set forth in the Office action mailed on May 28, 2026 and for the reasons stated below.
Applicant's arguments filed on August 27, 2026 have been fully considered but they are not persuasive. Applicant argues that Schwartz does not identify CES1; Moiseyev “does not provide a reasoned basis to expect” a therapeutic effect of increasing CES1 expression; and Blanks does not cure the deficiencies of Schwartz and Moiseyev. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As explained in the last Office action, the goal of increasing reverse cholesterol transport (or efflux of lipid) from RPE cells by overexpressing a gene encoding a therapeutic polypeptide for AMD treatment was art-recognized as evidenced by Schwartz, and CES1 was suggested to provide the therapeutic role as evidenced by Moiseyev. Further, Blanks teaches the level of skills/techniques pertaining to RPE-directed gene therapy. Hence, the combination of the cited references provides both a motivation and a reasonable expectation of success in arriving at the claimed subject matter. Applicant argues that the instant specification is “the only source” for the nexus between CES1 and RPE cholesterol efflux. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that the instant specification demonstrates that “CES1 exhibited the largest expression change between DHRD and healthy iRPE cells” by pointing out Example 2 and Figures 2D-2G and 7-8 and also additionally points out Example 4 and Figures 3F-3K as providing support that “increasing CES1 expression reduces a disease-associated lipid-accumulation phenotype.” It is unclear to the examiner how or why the disclosure of the instant application pointed out by applicant supports applicant’s asserted nonobviousness of the rejected claims. If applicant meant to assert unexpected results, applicant’s attention is directed to the fact that the rejected claims in the instant rejection are not directed to treating DHRD, and furthermore, what was pointed out by applicant pertains to mere in vitro cell culture experiment results. Hence, the data pointed out by applicant are not commensurate in scope with the rejected claims. Note that the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” See MPEP §716.02.
Applicant argues that the examiner has acknowledged a high level of unpredictability as noted in the §112(a) rejection of record such that there is “no prior art” that teaches the claimed method was well-known. In response, it is noted that applicant has taken the single sentence in the §112(a) rejection of record out of context. Note that the presence of “no prior art” pertains to statement that the “prior art knowledge pertaining to the required nexus between CES1 activity in RPE cells and the treatment, prevention, and cure of any given neurodegenerative disease including but not limited to Alzheimer’s disease, ALS, ataxia, dementias, Parkinson’s disease, Huntington’s disease, and neurotoxic injury was non-existent.” See page 6 of the last Office action. Furthermore, it was clearly indicated in the last Office action that the instant §103 rejection solely and strictly pertains to “macular degeneration”, which was excluded from the “no prior art” mentioned in the §112(a) rejection of record. Hence, applicant’s misplacement of the “no prior art” knowledge pertaining to non-macular degeneration diseases cannot whatsoever support the alleged high level of unpredictability for the instantly amended claims, which were exactly the basis for applying the instant rejection.
In view of the foregoing, this rejection is maintained.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 12-13, 15-16, and 18-25 are rejected under 35 U.S.C. 103 as being unpatentable over Schwartz et al. (US 7,470,659 B2, of record) in view of Galloway et al. (PNAS, 2017, E8214-E8223, applicant’s citation), Moiseyev et al. (Investigative Ophthalmology & Visual Science, 2015, 56:5506, of record), and Blanks et al. (US 2012/0077870 A1, of record).
Schwartz teaches a method of treating age-related macular degeneration (AMD) including “dry AMD”, wherein the method comprises administering a therapeutic composition that is able capable of “increasing reverse cholesterol transport in the retinal pigment epithelium (RPE)”, “thereby reducing accumulation of lipids in both retinal pigment epithelium and Bruch’s membrane”, wherein reverse cholesterol transport “may be important in the pathogenesis of AMD because of lipid efflux from RPE into Bruch’s membrane.” See columns 1-3 and 8.
Schwartz teaches that the therapeutic composition can be “a polynucleotide encoding the desired polypeptide”. See column 15.
Schwartz teaches that “reverse cholesterol transport” means “efflux of lipid from RPE cells”. See column 6.
Schwartz teaches that a person of ordinary skill in the relevant art “recognizes that such accumulations are a major finding in age-related macular degeneration (AMD), and therefore, recognizes the need for novel compositions for the treatment of this debilitating disease.” See column 3.
Schwartz does not teach that the “novel compositions” for treating AMD by increasing reverse cholesterol transport in the RPE include a DNA encoding CES1 in an AAV vector comprising an RPE-specific promoter such as RPE65. Schwartz also does not teach treatment of DHRD.
Galloway teaches that “DHRD patients have shown abnormal lipid- and protein-rich sub-RPE deposits (drusen)” and that both AMD and DHRD have “striking similarities” in “symptoms, pathology, and functional loss” and that both are characterized by “the accumulation of drusen, lipoproteinaceous aggregates localized between the RPE and its underlying ECM, the Bruch’s membrane in the eye.” See pages E8215 and E8221.
Moiseyev teaches that carboxylesterase-1 (CES1) is expression in the human RPE and functions as “a retinyl ester hydrolase in the RPE” thus “CES1 may have a physiological role in mobilization of retinol from the RPE lipid droplets”. See the entire abstract.
Blanks teaches that an AAV vector comprising an “RPE-specific promoter” (e.g., “RPE65”) that is operably linked to a polynucleotide sequence encoding a therapeutic polypeptide is capable of producing a therapeutically sufficient amount of the polypeptide in the eye, specifically the RPE, wherein the AAV vector can be “locally injected into the targeted region of the eye, via an appropriate route such as subretinal”. See paragraphs 0054, 0111-0112, and 0164; claims 1, 10, 15, 17; FIG 7.
It would have been obvious to one of ordinary skill in the art before the effective filing date to subretinally inject an AAV vector comprising an RPE-specific promoter such as RPE65 operably linked to a polynucleotide encoding CES1 when practicing Schwartz’s dry AMD treatment method that uses “a polynucleotide encoding the desired polypeptide” for increasing reverse cholesterol transport (or efflux of lipid) from RPE cells. One of ordinary skill in the art would have reasonably understood that a polynucleotide encoding CES1 qualifies as Schwartz’s “polynucleotide encoding the desired polypeptide” that increases lipid efflux from RPE cells because CES1 was suggested to “have a physiological role in mobilization of retinol from the RPE lipid droplets” as evidenced by Moiseyev. As such, one of ordinary skill in the art would have been motivated to make and administer an AAV vector comprising an RPE-specific RPE65 promoter operably linked to a CES1-encoding polynucleotide via subretinal injection with a reasonable expectation of success in order to effectively express CES1 in the RPE of an eye of a subject in need of treatment for dry AMD because investigating and using a “novel” composition that increase lipid efflux (or reverse cholesterol transport) from the RPE cells for treatment of AMD was an art-recognized goal as evidenced by Schwartz, and because an AAV vector comprising an RPE-specific RPE65 promoter operably linked to a therapeutic protein-encoding sequence was known to provide therapeutically sufficient amount of the protein in the RPE of an eye of a subject when subretinally injected as taught by Blanks.
It would also have been obvious to one of ordinary skill in the art to apply the subretinal injection of the CES1-encoding AAV vector rendered obvious as explained above to a subject having DHRD because one of ordinary skill in the art would have reasonably deemed that increasing efflux of RPE lipid droplets, which contribute to the development/accumulation of drusen that is the hallmark of both AMD and DHRD, would be also therapeutically applicable to DHRD treatment because it was art-recognized knowledge that both AMD and DHRD pathologies have “striking similarities” in “the accumulation of drusen, lipoproteinaceous aggregates localized between the RPE and its underlying ECM, the Bruch’s membrane in the eye” as taught by Galloway thus would have reasonably expected that the method rendered obvious above would be also therapeutically useful in the treatment of DHRD.
Accordingly, claims 12-13, 15-16, and 18-25 taken as a whole would have been prima facie obvious before the effective filing date.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, RAM SHUKLA can be reached at 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DANA H SHIN/Primary Examiner, Art Unit 1635
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