DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This office action is in response to a claim set filed 11/2/2022. The claim set filed with the substitute specification 9/7/2023 is the original and not amended claims.
Claims 104-135 are pending.
The present application is a divisional of U.S. Patent Application No. 17/242,357, filed April 28, 2021, not U.S. Patent 11,535,868, which claims benefit of U.S. provisional application 63/017,148 filed 4/29/2020.
Information Disclosure Statement
An IDS filed 7/13/2023 has been identified and the documents considered. The signed and initialed PTO Form 1449 has been mailed with this action.
There are three notations on the IDS. First, if the document has been identified and considered, it is initialed. In the case that the document could not be located, it has been crossed off of the IDS. A search of the prior references as well as those submitted with this application were scanned. The document lined through could not be found in the cases. As these appear to be missing from the file, it would be remedial to include a copy and a new 1449 with their listing in the response. Third, for the document listed as a Search report, it has been considered but has been crossed off of the Form 1449.
Sequence Compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below or on the attached Notice To Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures. Specifically, pages 102 and 104 contain sequences that are not identified by sequence identifier numbers. If the sequences can be found in the sequence listing it would be remedial to insert the appropriate SEQ ID NO:s. If not, a substitute paper copy of the “Sequence Listing”, as well as an amendment directing its entry into the specification, CRF and letter stating that the contents of the sequence listing and the CRF are the same and contain no new matter is required. The nature of the non-compliance did not preclude the examination on the merits of the instant application, the results of which follow.
Claim Objections
Claim 1 is objected to because of the following informalities: when using abbreviated terms, the first occurrence should be spelled out such as “C5-12(T)”. Thereafter, the abbreviation should be used such as rAAV in claim 111 and ITR and AAV in claim 113. Independent limitations require their own articles such as “second ITR” in claim 109, 110, 114 and 115.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 108 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 108 recites the limitation "the nucleic acid molecule" in claim 107. There is insufficient antecedent basis for this limitation in the claim. There are two references to nucleic acid molecules which may or may not be overlapping but as recited are not. Hence, by reference “the nucleic acid molecule it is unclear to which the claims refer.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 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 104-135 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a nucleic acid molecule comprising an alphavirus replicon RNA with the nucleotide sequence of SEQ ID NO:2-18 in which the U2 position of any of SEQ ID NO:2-18 is substituted with a G and wherein at least a portion of the alphavirus genome is deleted such that at least one structural protein is not encoded, does not reasonably provide enablement for any other embodiment. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims are drawn to gene therapy method of treating a disease or condition wherein the gene encodes a modified mini-dystrophin peptide.
2) Scope of the invention. The scope of the invention is extremely broad in reference to the disease or condition and to the “nucleic acid molecule” but the encoded peptide is restricted by being 98% identical to the amino acid sequence of SEQ ID NO:83. The peptide comprise specifically a part of the R16 domain replaced by the corresponding domain of R2. In dependent claims the nucleic acid molecule is defined further by promoter, intron, UTR and polyA sequence an as well being part of a rAAV. The disease is limited in claim 118 to dystrophin deficiencies that fit a broad list in claim 119. Finally, claims 12,3127, 131 and 135 recite functional outcomes that are recited in terms of desired outcomes wherein steps top accomplish the outcome are omitted and hence these claims lack adequate description for the genus of potential means to reach.
3) Number of working examples and guidance. Example 1 identifies a const5urct defined by the claims.
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This peptide was highly expressed in vitro (example 2) and induced a significant increase in CD4+ and CD8+ proliferating T cells (example 3). A construct was designed (example 4 and 5) by codon optimization and inclusion of a C5-12T promoter and SV40 intron. AAV9 constructs comprising thereof expressed in muscle tissue such as heart, diaphragm and tibialis anterior. In vitro the construct improved conduction velocity (example 7) and in vivo mice models demonstrated efficient expression in striated muscle with variable regeneration. Example 9 -14 showed that expression of min-dystrophin resulted in restored glycoprotein complex, nNOS, normal muscle mass, prevention of synaptic fragmentation, normal creatine kinase levels and normal strength.
4) State of the art. Dystrophin stabilizes the muscles during contraction. Deficiencies of dystrophin is the cause of a spectrum of disorders called dystrophinopathy. Duchenne muscular dystrophy (DMD) is the most common form. It is caused by pathogenic variants in the DMD gene that result in dysfunctional dystrophin resulting in impaired motor function. Attempts at correction have not been successful but have centered on use of micro-dystrophin or smaller versions of the gene (Keselman, Current Treatment Options in Neurology, 2025, pages 1-10). This is because the gene is itself extremely large, the cDNA is about 13.9 Kb (see disclosure ¶0006). AAV can only transfer 4.9 kb. The history of gene therapy of DMD has focused on DMD delivery. At the time of filing standard of care for DMD is steroid therapy (see bridging ¶ page 532-533 of Heier et al, Journal of Cachexia, Sarcopenia and Muscle 2023 page 940–954).
5) Unpredictability of the art. The claims are drawn in their broadest to treatment of any disease or disorder and at their most narrow a number of dystrophin deficiencies. It is not a reasonable approach to treat any disease or disorder with dystrophin as the administration of this protein provides no generic benefit based on the disclosure and the art for any disease or disorder. To this end, even the list of deficiencies of claim 119 (Sarcopenia, a heart disease, cachexia, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy (XLDC), facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, limb-girdle muscular dystrophy, oculopharyngeal muscular dystrophy, Emery-Dreifuss muscular dystrophy, distal muscular dystrophy, and/or congenital muscular dystrophy) is a list that presents an extremely large genus. First, these disorders are genetically and phenotypically diverse. Considering even just the difference between BMD and DMD, the use of gene therapy has not applied as BMD already produces a shortened dystrophin (see page 941, col 1 Heier et al) and the micro-dystrophin delivery will not benefit them as they are designed ot overcome complete lack of dystrophin as found in DMD patients .
Secondly, the disclosure does not support treatment of the large genus. Rather, the results are provided in a limited set of examples focusing on mdx mice which is an DMD model due to a point mutation in the DMD gene resulting in a dystrophin deficiency. Hence, one cannot corelate the disclosure results with the large genus. As set forth in the MPEP, the results must correlate with the claimed disorder.
The issue of "correlation" is related to the issue of the presence or absence of working examples. "Correlation" as used herein refers to the relationship between in vitro or in vivo animal model assays and a disclosed or a claimed method of use. An in vitro or in vivo animal model example in the specification, in effect, constitutes a "working example" if that example "correlates" with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute "working examples.".
The art demonstrates this as well (see Heier et al, bridging ¶ col 1-2, page 941).
Hence, considering just DMD, the development of gene therapy has been intensive with promising results as well as obstacles. Considering the broadest claim with the delivery of any nucleic acid, this has shown very little promise due to numerous obstacles i.e. organ barriers, failure to persist, side-effects in other organs, virus neutralizing antibodies, humoral immunity, normal tropism of the vector to other organs and more. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. The inability to develop an adequate means of overcoming obstacles such as humoral; responses and refractory cells limits the successful means by which the nucleic acid can be administered (see Rando et al, Biochimica et Biophysica Acta 1772 (2007) 263–271, see page 264, col 1-2).
AAV development and modifications have been focused on due to the ability to delete all of the non-essential genes for the large insert and the protection the coat offers (Bengtsson et al, Molecular Therapy, 2025, pages 2035-2051, see page 2037). While great promise has been demonstrated by AAV, there has been a lack of translational demonstration from mice models highlighting the unpredictable nature of the inventio. Bengtsson et al teach "Generating transgenic mice is not a clinically useful gene therapy, however, and numerous labs began searching for methods to deliver dystrophin expression cassettes to muscles of neonatal, adolescent, and adult mice." NHPs are commonly used for pre-clinical pharmacokinetic (PK) and toxicological assessments of therapeutic AAV vectors under the assumption that AAV behaves similarly in NHPs and humans (Liu, Molecular Therapy: Methods & Clinical Development Vol. 33 March 2025, page 1-10 see page 3). Largely, issues of delivery and translation lagged wherein there demonstrated an inability to target muscles body-wide, including the heart (Bengtsson et al, page 237). Because of their tropism to muscle, AAV8, AAV9 and AAV rh74 have become primary carriers for DMD therapy via an intravenous route (see Chwalenia et al, Gene Therapy (2025) 32:447–461). To date, clinical results have been varied (see Chwalenia et al, page 451 and page 456) bringing into question timing of delivery and immune reactions.
Third considering claims 123, 127, 131 and 135, the claims are simply drawn to desired results. However, it is not clear what adjustments must be performed to alter the simply administration of the nucleic acid or AAV to the subject wherein the effects of 2-fold to 100 fold increase in dystrophin protein expression is achieved. Hence, applicants have not demonstrated this range of expression nor means to accomplish these goals. While the results presented in the art do not necessarily preclude Applicant's hypothesis, they certainly fail to support it. Consequently, the prior art (and post-filing art) when combined with the lack of any disclosed direct experimental test of Applicant's hypothesis, shows that one of skill in the art at the time the invention was made would have had no basis to reasonably predict or conclude the claimed invention would succeed. There is no evidence that the specification offers a solution to the problem set forth in the specification. Though not controlling, the lack of working examples, is, nevertheless, a factor to be considered in a case involving both physiological activity and an undeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, he runs the risk that unless one with ordinary skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them. Ex parte Sudilovsky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).
6) Undue experimentation. The claims have been evaluated in light of the art at the time of filing and found not to be commensurate in scope with the specification. MPEP 2164.05 teaches, “However, the examiner should carefully compare the steps, materials, and conditions used in the experiments of the declaration with those disclosed in the application to make sure that they are commensurate in scope; i.e., that the experiments used the guidance in the specification as filed and what was well known to one of skill in the art. Such a showing also must be commensurate with the scope of the claimed invention, i.e., must bear a reasonable correlation to the scope of the claimed invention. The invention recites use of a broad group of sequence. Given the unpredictability of the art, the poorly developed state of the art with regard to predicting the structural/ functional characteristics of antagonists, the lack of adequate working examples and the lack of guidance provided by applicants, the skilled artisan would have to have conducted undue, unpredictable experimentation to practice the claimed invention.”
Consequently, the prior art (and post-filing art) when combined with the lack of any disclosed direct experimental test of Applicant's hypothesis, shows that one of skill in the art at the time the invention was made would have had no basis to reasonably predict or conclude the claimed sequences could be identified given the lack of details necessary to identify those meeting the necessary functions. Though not controlling, the lack of working examples, is, nevertheless, a factor to be considered in a case involving both physiological activity and an undeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, he runs the risk that unless one with ordinary skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them. Ex parte Sudilovsky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).
The court and the Board have repeatedly held (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eli Lilly & Co., 43 USPQ2d 1398 (CA FC, 1997)) that an adequate written description of a nucleic acid requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method; what is required is a description of the nucleic acid itself. It is not sufficient to define DNA solely by its principal biological property, because disclosure of no more than that, as in the instant case, is simply a wish to know the identity of any DNA with that biological property. Naming a type of
material generically known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material. When one is unable to envision the detailed constitution of a complex chemical compound having a particular function, such as a nucleic acid, so as to distinguish it from other materials, as well as a method for obtaining it, conception has not been achieved until reduction to practice has occurred, i.e., until after the nucleic acid has been isolated. Thus, claiming all DNA's that achieve a result without defining what means will do so is not in compliance with the description requirement. Rather, it is an attempt to preempt the future before it has arrived. Also, where a claim purports to cover all nucleic acids that encode a specific protein and the specification discloses but a single DNA known to do so, the situation is analogous to a single means claim and does not meet the enablement requirement under para. 1 ' of§112. Specifically, in the instant case, the specification provides SEQ ID NO: 1.
Applicants have created a single modified VEEV RNA replicon in which the U2 is modified to G. This replicon has enhanced expression activity. The analysis is limited to VEEV wherein the evidence in fact is only a single nucleotide substitution. Applicants have provided no evidence that it can be extrapolated to any other sequence. While it is routine to screen for variants comprising multiple substitutions/multiple modifications, the specific modifications that can be made with a reasonable expectation of success in obtained the desired activity are limited and the result of such modifications is unpredictable. As discussed above, predictability of which changes can be tolerated in a sequence and obtain the desired activity requires a specific knowledge of and guidance with regard to which specific sequences can be modified such that the modified sequence continues to have said claimed activity. It is this specific guidance that applicants do not provide. While the art may teach general mutagenesis techniques, such teachings will not reduce the burden of undue experimentation on those of ordinary skill in the art at arriving at the claimed invention
Conclusion
Co-owned application 17/288,029 now U.S. Patent 12,680,108 teaches a mini dystrophin protein with an R16 domain and no R2 domain. Hence, it does not read on an R16 mutated by comprising R2 sequences.
Parent application is drawn to the sequence used in the method which is 98% related to SEQ ID NO:83. This application, of which the instant is a divisional, is now U.S. Patent 11,535,868.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIA MARVICH whose telephone number is (571)272-0774. The examiner can normally be reached 8 am - 5 pm.
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/MARIA MARVICH/Primary Examiner, Art Unit 1633
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