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/Election/Restrictions
Applicant’s election with traverse of Group II (Claims 5964) in the reply filed on 6/29/2026 is acknowledged. Applicant’s traversal is on the grounds that, although the claims are distinct, all of the claims recite exactly the same AAV vectors and related mechanisms of action and thus encompass overlapping subject matter and would not present any undue burden in examining the claims together. This is not found persuasive because methods for inducing differentiation of a myofibroblast, treating liver fibrosis and restoring tissue specific function to fibrotic tissue in an organ are all distinct methods with materially different design, mode of operation, function, or effect; (2) the inventions do not overlap in scope, i.e., are mutually exclusive; and (3) the inventions as claimed are not obvious variants, see MPEP § 806.05(j). Accordingly, there is a search and examination burden to search these inventions in the same application. The requirement is still deemed proper and is therefore made FINAL. Claims 53-72 are pending. Claims 53, 55, 59 and 62 have been amended. Claims 53-58 and 65-72 are currently withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 59-64 are the subject of the present Official action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO/085,177, 371 of PCT/US2015/062841 and CON of 15/531,341 filed on 11/26/2014, 11/27/2015 and 5/26/2017, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as on 11/26/2014.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6/11/2024 were received. The submissions were in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements were considered by the examiner.
Claim Rejections - 35 USC§ 112, Scope of Enablement
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 59-64 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating liver fibrosis comprising administering a therapeutically effective amount of the claimed composition, does not reasonably provide enablement for a method for the complete prevention of liver fibrosis comprising administering a prophylactically effective amount of the claimed composition. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the claimed method for the complete prevention of liver fibrosis as presently claimed. This rejection is supported by the disclosure of Yu et al, US20130251694A1, published 9/26/2013 (hereinafter Yu).
The factors listed below have been considered in the analysis of enablement:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The terms “preventing” and “prophylactically effective amount” embraces a range of possible patient outcomes from total to partial prevention of liver fibrosis. The instant specification does not provide sufficient examples, protocols and outcomes relating to an enabling disclosure for methods to completely prevent liver fibrosis by administering one or a plurality of AAV vectors comprising HNF4α and one or more of FOXA1, FOXA2, HNF1α, HNF6, GATA4, HLF, CEBPA, PROX1 and ATF5A. The examiners search of the prior art finds no supportive evidence of any complete prevention treatment for liver fibrosis. For example, the examiner has identified Yu as a reference directly related to the claimed methods. Yu describes how liver fibrosis and cirrhosis result in the scarring of tissue and physically alters the livers architecture and blood supply (Yu, para 231, 242). Ultimately, this may change the livers architecture and blood supply, thus affecting vector uptake and make the total prevention of liver fibrosis across the breadth of possible outcomes extremely unpredictable. It is emphasized that the claim to prevention has a higher requirement for an enabling disclosure than a claim to a treatment. An amendment to change the word prevention to treatment and prophylactically effective amount to therapeutically effective amount would be remedial. Should the applicant disagree with the above enablement analysis, the applicant is invited to submit prior art to support the statement of complete prevention if liver fibrosis. According, since both the instant specification and prior art are silent on methods for the complete prevention of liver fibrosis, the scope of prevention is not enabled.
Claim Rejections - 35 USC § 112b
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 62 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 62 describes one or a plurality of AAV vectors which encode for “one or more nucleic acid molecules” which encode for the first and second nucleic acid sequences. It is unclear if “one or more” nucleic acid molecules requires one or multiple copies of the first and/or second nucleic acid sequence. As a result, one of ordinary skill would not understand if only a single or multiple copies of the first and/or second nucleic acid sequence is required in the first and/or second AAV vector. Please note that the language of a claim must make it clear what subject matter the claim encompasses to adequately delineate its "metes and bounds", see MPEP 2173.
Claim 64 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 64 describes an AAV capsid comprising VP1, VP2 and VP3 capsid polypeptides from AAV6 for a functional fragment thereof comprising at least about 90% sequence identity to VP1, VP2 and VP3. However, the claims fail to describe a corresponding SEQ ID NO. As a result, one of ordinary skill would not understand which SEQ ID should be at least about 90% identical to meet the claim limitations. Please note that the language of a claim must make it clear what subject matter the claim encompasses to adequately delineate its "metes and bounds", see MPEP 2173.
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 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.
Claims 59 and 62-63 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Fox et al, US 2014/0249209, published 9/4/2014 (hereinafter Fox).
Claim 59: Fox describes methods for treating hepatic fibrosis and cirrhosis via the administration of an AAV vector encoding HNF4α in conjunction with transcription factors like FOXA1, FOXA2 and CEBPα (Fox, para 4, 8, 9 and 64). Fox states that late stages of cirrhosis are characterized by portal hypertension and hepatic encephalopathy, terminal extrahepatic processes that result from fibrosis and vascular remodeling of the cirrhotic liver (Fox, para 4). Fox defines HNF4α and functional fragments thereof as any agent which regulates HNF4α expression, including a nucleic acid sequence which encodes HNF4α (Fox, para 25-27). Fox describes the administration of these AAV vectors with a pharmaceutically acceptable carrier (Fox, para 81).
Claims 62-63: Fox describes using a second viral vector and multiple administration regiments via subcutaneous injection as needed, reading on a second AAV vector (Fox, para 90, 118 and 127). Fox describes administering HNF4α “in combination” with other transcription factors including HNF1α, FOX2A or CEBPα among others embraces the use of a second and third transcription factor (Fox, para 8, 9, 21, and 87 and claim 8).
Claim Rejections - 35 USC § 103
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 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 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.
Claims 59-64 are rejected under 35 U.S.C. 103 as being unpatentable over Fox (supra) in view of Linden et al. US 2018/0135076, published 5/17/2018, Wu et al. "Single amino acid changes can influence titer, heparin binding, and tissue tropism in different adeno-associated virus serotypes." Journal of virology 80.22 (2006): 11393-11397 and Iwaisako et al. "Origin of myofibroblasts in the fibrotic liver in mice." Proceedings of the National Academy of Sciences 111.32 (2014): E3297-E3305 (hereinafter Iwaisako).
A description of Fox can be found above with respect to claims 59 and 62-63. Fox describes expression in the fibrotic liver and states that “somatic cells can be reprogrammed into pluripotent stem cells and fibroblasts or hepatocytes can be reprogrammed into other mature cell lineages following the forced expression of selected transcription factors” but does not expressly mention the direct conversion of myofibroblasts into hepatocytes (Fox, para 5). Fox describes using AAV vectors, but does not expressly describe the use of viral capsids from AAV6 comprising VP1, VP2 and VP3
Claim 64: Linden describes recombinant AAV6 vectors and capsid proteins thereof which are suitable for the delivery of therapeutic genes in vivo (Linden, para 32, 33, 138, 147, 151). Linden teaches "An 'AAV virus' or 'AAV viral particle' or 'rAAV vector particle' refers to a viral particle composed of at least one AAV capsid protein (typically by all of the capsid proteins of a wild-type AAV) and an encapsulated polynucleotide rAAV vector (Liden, para 105). It is noted that AAV6 vectors inherently comprise VP1, VP2 and VP3 capsid proteins (Linden, para 110 and 318). Linden teaches one of the most prominent characteristics of various rAAV serotypes is their tissue tropism (Liden, para 3, 5, 0329). Linden provides motivation for incorporating VP polypeptides to increase viral infectivity. Linden specifically describes VP1 polypeptides of AAV6 (Linden, para 302). Linden describes the various advantages of each AAV variant and how a transgene of interest may be inserted (Linden, para 101, 138, claim 15).
Claim 64: To emphasize the known connection between AAV serotype selection and tissue tropism for the delivery of therapeutic genes in vivo, Wu is described herein. Wu describes how single amino acid changes can influence tilter, heparin binding and tissue tropism among different AAV serotypes (Wu, abstract). Wu states that despite the high degree of sequence homology between AAV1 and AAV6 capsids, the two serotypes display varying tissue tropism, with AAV6 vectors displaying an increased liver transduction when compared to AAV1 and other serotypes (Wu, pg 11393 para 2).
Claims 60 and 61: Iwaisako describes how hepatic myofibroblasts are activated in response to chronic liver injury (Iwaisako, abstract).
It would have been prima facie obvious to one of ordinary skill in the art use serotype AAV6 as described by Linden and Wu comprising endogenous VP1, VP2 and VP3 capsid proteins with the gene therapy treatment methods for treating fibrotic liver disease outlined by Fox given the known tissue tropism exhibited by AAV6 serotypes. It would have been a matter of simply substituting one AAV variant for another since Fox describes the use of AAV vectors without indicating a particular variant. Linden experimented with numerous AAV variants showing that transgene insertion into any particular AAV variant is common in the art. One would have been motivated to make such a substitution in order to optimize transduction efficiency, since Linden shows that each variant has a variable transduction efficiency in each corresponding tissue type (Linden, para 229). As shown by Iwaisako, myofibroblasts would inherently be present in the fibrotic liver tissue and would therefore be transduced and converted into normal healthy hepatocytes. One would have a reasonable expectation of successes given the well-established methodologies for AAV gene insertion and the fact that Fox achieved favorable results using AAV vectors. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634
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