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 .
Claims 44-54 are pending in the application.
This office action is in response to the amendment filed on 10/14/2025.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 44-54 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
The nature of the invention
The claimed invention of claim 44 and 48 is drawn to a method that can treat retinitis pigmentosa (RP) in a human subject, comprising administering to said subject a composition that comprises a recombinant adeno-associated virus (rAAV) comprising a promoter operably linked to a nucleic acid encoding NFE2L2/Nrf2, wherein the composition is formulated for intraocular administration.
The breadth of the claim
The claim scope encompasses treating retinitis pigmentosa in human subject, by administering an AAV encoding Nrf2.
The teaching from the specification and the presence of working examples
The specification teaches methods that inhibits oxidative stress of photoreceptor cell with antioxidant defense protein including Nrf2 can treat or prevent disorders associated with cellular oxidative stress. The specification teaches Nrf2 is expressed at a very low level in photoreceptors and other retinal cells in normal retinas, but elevated in rod photoreceptor cell death phase of the retinal degeneration (page 59, lines 20-25). The specification demonstrated that overexpression of Nrf2 by AAV vectors prolongs cone survival in rd1 mouse retinas at p50, and co-expression of Nrf2 and PGC1α rescued cone survival in the central retina at p50 (page 59, last paragraph). The specification teaches mice overexpressing Nrf2 exhibits better overall photoreceptor function. However, the specification does not teach whether expressing Nrf2 in other animal model of RP or human RP patient can treat RP disorder. As such, whether administering a single agent Nrf2 can treat RP in human subjects is unpredictable.
The state of prior art and the level of predictability in the art
The art teaches RP is a heterogeneous group of hereditary diseases that lead to the degeneration of retina’s photoreceptor cells, starting with rods, resulting a gradual loss of vision over time (Wu et al., Pharmaceutics 2023, vol. 15, no. 685, pages 1-32, page 1 1st paragraph, line 1-3). Wu et al. teach that RP can be classified into two categories: syndromic and non-syndromic, wherein syndromic is caused by sporadic mutations and genetic predisposition, and syndromic RP is caused by hereditary mutation (page 2, section 2.2). Wu et al. teach the prognosis of RP is difficult to establish because of the heterogeneity of gene mutations, and the disease progression can vary depending on specific gene mutations and other factors with onset of symptoms in childhood or in adulthood (page 2, section 2.3). Wu et al. teach there is currently no curative treatment for most patient with RP (page 3, 2nd paragraph), 10 years after the filing of the present application. With regard to gene therapy to RP, Wu et al. teach that Luxturna is the only approved gene therapy for RP, targeting mutation in a specific gene RPE65. Wu et al. teach that in early stages of RP, a combination of various treatments including antioxidants and neuroprotective agents can slow the progression of the disease (page 17, paragraph 8).
According to the knowledge in the art, it is clear whether there is agent(s) can prevent the development of RP is unpredictable because RP is a hereditary disorder. Due to the heterogeneity of the mutation(s) that causes RP, whether a single agent Nrf2 can treat all types of RP, especially human subjects is unpredictable.
The amount of experimentation
In view of the art recognized unpredictability, a skilled artisan would have to rely solely on the guidance from the specification to practice the method as claimed. However, the specification only showed one specific mouse model, rd1, with one type of mutation, that Nrf2 is able to increase the survival of cone receptor. The skilled artisan would thus need to engage in experimentation to extend the study to determine whether Nrf2 can treat RP caused by other types of mutation(s), and such experimentation would have been undue because of the unpredictability in the art, even 10 years after the filing of the present application. Therefore, the claimed method treating RP in a human patient, is not enabled by the present application.
Response to Arguments
Applicant argues that applicant’s invention is based on part on the discovery that increased expression in certain genes in a photoreceptor cell undergoing oxidative stress can serve to fight oxidation and/or detoxify free radicals. Applicant argues that the specification teaches at page 25, line 33, through page 26 that administering the agents for the purpose of “curing, healing, alleviating, relieving…the condition is also ‘treated’ if recurrence of the condition is reduced, slowed, delayed or prevented.” Applicant states that claim 1, and dependent claims are directed to a method for treating retinitis pigmentosa in a human subject comprising administering to said subject a recombinant AAV comprising a promoter operably lined to a nucleic acid molecule encoding Nrf2 in an amount effective for promoting photoreceptor survival and/or function of a photoreceptor cell compromised by retinitis pigmentosa. And claim 5 is directed to a method for treating retinitis pigmentosa in a human subject comprising administering to said subject a recombinant AAV comprising a promoter operably lined to a nucleic acid molecule encoding Nrf2 in an amount effective for prolonging the viability of a photoreceptor cell compromised by retinitis pigmentosa. Applicant argues that the working examples demonstrate that photoreceptor require robust anti-oxidation capacity provided by anti-oxidant defense genes for survival, citing example 1. The specification demonstrated that anti-oxidant defense gene, Nrf2, is expressed at very low level in photoreceptors and other retinal cells in normal retinas, but Nrf2 protein is elevated during rod photoreceptor death phase of the retinal degeneration. Applicant asserts that in two different art recognized mouse models of RP has distinct genetic mutations, the specification demonstrated that Nrf2 protein levels were elevated in cones in both model, rd10, and Rho-/-. Applicant argues that increased Nrf2 protein in cones is a general problem for retinal degeneration disease. Applicant asserts that overexpressing Nrf2 by administration of pharmaceutical composition comprising viral vector provides a more durable effect in promoting cone survival, preserving cone outer segments, and photoreceptor function in another relevant mouse RP model, RP1 mouse. Applicant argues that the specification demonstrates in rd1 mouse that an AAV vector comprising overexpressing Nrf2 prolonged cone survival in retinas at p50 as determined by cone density and preserved cone outer segments. Applicant asserts that overexpression of Nrf2 reduces superoxide levels, lipid oxidation in rd1 mice, and in rho-/- mice at p100, the injected eyes with AAV vector overexpressing Nrf2 have significantly higher visual acuity than uninjected eyes. Applicant argues that the specification provides teachings to determine whether a subject having retinitis pigmentosa is treated by, reducing at least one symptom associated with the disorder, for example prolonging the viability of a photoreceptor cell compromised by retinitis pigmentosa in the subject either long term or short term of simply a transient beneficial effect to the subject, and methods for monitoring the vision. Applicant argues that clinical trials are not required, Applicant argues that the specification provides sufficient teaching to the claimed method of treating RP in human subject.
The above arguments have been fully considered but deemed unpersuasive. Since claims 1 and 5 were canceled, presumably that the discussion of these claims are referring to claims 44 and 48. While the specification studied the relationship between Nrf2 and oxidative damage to photoreceptor cells, the fact that elevated level of Nrf2 during retina degeneration but not in normal retinal tissue in mouse model does not suggest that overexpression of Nrf2 may predictably provide treatment to RP in human patient. As known in prior art, RP is a heterogenous group of hereditary diseases characterized by progressive degeneration of retinal photoreceptors, which makes providing a single treatment to RP with a wide variety of causes unpredictable. Wu et al. also indicates that “the difficulty with antioxidation when it comes to neuroprotection is the dosage of the drug, and most of these studies are performed at early stages of the disease” and “many treatments using neuroprotective agents have been tested on mice as the therapy is well-tolerated and has few side effects” (page 30, 2nd paragraph). Wu indicates while many different therapies have shown promising results in vitro and animal models, it only “offer the hope of reversing the damage, restoring vision and revolutionizing the way RP is treated.” (page 22, 5th paragraph). So even 10 years after the filing of the present application, there is no established correlation between in vitro or animal model result which can provide predictive success in human RP treatment. As such, whether testing some potential therapy on a couple of mouse models of RP would yield predictable results in human subject would have been unpredictable at the time the application was filed. Therefore, this rejection is maintained for reason discussed previously and set forth above.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119 (e) and 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 61/896,805, 15032,426 and 17/206,212 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application (see 112 a rejection above).
Accordingly, claims 44-54 are not entitled to the benefit of prior applications. The effective filing date for claims 44-54 is the actual filing date of the present application 4/19/2024.
Response to Arguments
Applicant provides the same argument as directed to the enablement rejection set forth above. They are not persuasive for reason discussed above.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 44-54 is/are rejected under 35 U.S.C. 102(a1)(a2) as being anticipated by Bennett (US 11,879,133).
Bennett teaches a composition that comprise a recombinant adeno-associated virus comprising a promoter operably linked to a nucleic acid encoding Nrf2 (col.1, lines 55-60). Bennett teaches the promoter is specific for expression of the transgene in photoreceptor cells, such as rod and cones, and gives an example of human rhodopsin kinase promoter (col.20, lines 25-34). Bennett teaches the AAV may be AAV2/8 (col.16, lines 43-44). Bennett teaches said composition is formulated for intravitreal delivery (col.27, lines 21-24). Bennett teaches said composition may be used to treat a variety of optic disorder including retinitis pigmentosa (col.5, lines 65-67). Therefore, the disclosure from Bennett anticipates claimed method of claims 44, 45, 47, 48, 49, 50 and 52.
Regarding claims 46 and 51, Bennett teaches the recombinant AAV is formulated as suspension (col.28, lines 31-38). Since the instant specification states that a viscosity inducing agent can be a suspension form [0201], the teaching from Bennett meets this claim limitation.
Regarding claims 53 and 54, the wherein clause does not further limit the claim because it does not set forth positive step(s) that is performed.
Response to Arguments
Applicant argues that the claimed invention is entitled to the priority date of 10/29/2013, which is earlier than the filing date of Bennett.
This is not persuasive for reason discussed above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 44-54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10,980,896. Although the claims at issue are not identical, they are not patentably distinct from each other because the composition claimed in claims 1 and 4 of ‘896 patent anticipates the composition used in the method of treating retinitis pigmentosa (RP) claimed in claims 44 and 48 of present application.
Regarding claims 45 and 50, claim 2 of the ‘896 patent recites same promoters.
Regarding claims 46 and 51, claim 3 of the ‘896 patent recites same limitation of including a viscosity inducing agent.
Regarding claims 47 and 52, claim 5 of the ‘896 patent recites same route of administration.
Regarding claim 49, claim 6 of the ‘896 patent recites same AAV vector.
Regarding claim 53 and 54, the composition recited in claims 1 and 4 of ‘896 is intended to prolong the survival and/or function of the photoreceptor cell.
Claims 44-54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12042546. Although the claims at issue are not identical, they are not patentably distinct from each other because the method claimed in claims 1-9 of ‘546 patent recites same steps as claimed in claims 44-54 of present application.
Response to Arguments
Applicant states that TD will be considered when the claims are indicated being otherwise allowable.
This rejection is thus maintained because no TD was filed.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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/CELINE X QIAN/ Primary Examiner, Art Unit 1637