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 .
Election/Restrictions
Applicant’s election without traverse of group I, claims 12-8 and 10-14 in the reply filed on 04/25/2025 is acknowledged.
Claims 15-16,19-22,24 and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 04/25/2025.
Claims 2-8 and 10-14 are under consideration.
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.
Claims 2-8 and 10-14 are 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 2 is unclear whether “wherein the subject has a recessive mutation …” is referring to a homozygous or heterozygous mutation. The specification supports carrying out the method in homozygous mutant mice that are “in need” of treatment. However, “a recessive mutation” refers to mutation of a single allele. Dependent claims are unclear for the same reason.
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 2-8 and 10-14 remains rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The specification has described the nucleotide sequence set forth by SEQ ID NO:1 and the nucleotide sequence encoding the amino acid sequence set forth in SEQ ID NO:2. The specification, however, has not described any variant sequences of the nucleotide sequence set forth in SEQ ID NO:1 or of the nucleotide sequence encoding the amino acid sequence set forth in SEQ ID NO:2 that are within the genus wherein such variants include nucleotide sequences having at least 85% identity to the nucleotide sequence set forth in SEQ ID NO:1, nucleotide sequences encoding amino acid sequences having at least 85% similarity to the amino acid sequence set forth in SEQ ID NO:2, any nucleotide sequence capable of hybridizing to the nucleotide sequence set forth in SEQ ID NO:1 or any fragments
In the instant case the Ano5 variants encompassed by the claims lack a written description. The specification fails to describe what DNA molecules fall into this genus that would retain Ano5 activity and it was unknown as of Applicants’ effective filing date that any of these DNA molecules would have the property of encoding the Ano5 polypeptide having the same structural and functional properties as that encoded by SEQ ID NO:1. The claimed embodiments of Ano5 variants encompassed within the genus lack a written description. There is no evidence on the record of a relationship between the structures of the nucleotide sequences coding for the Ano5 variants and the nucleotide sequence set forth by SEQ ID NO:1 or the Ano5 variants and the polypeptide sequence set forth by SEQ ID NO:2 that would provide any reliable information about the structure of DNA molecules within the genus. The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
With the exception of the sequence referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed polynucleotides or polypeptides, and therefore conception is not achieved until reduction to practice has occurred regardless of the complexity or simplicity of the method of isolation. The skilled artisan cannot envision the detailed chemical structure of the encompassed nucleic acid molecules and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The nucleic acid itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
In view of the above considerations one of skill in the art would not recognize that applicant was in possession of the necessary common features or attributes possessed by any member of the genus of Ano5 variants encompassed by the claims. Therefore, only the Ano5 gene encompassed by SEQ ID NO:1 and the corresponding polypeptide encompassed by SEQ ID NO:2, but not the full breadth of the claims meet the written description provision of 35 U.S.C. §112, first paragraph. University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that “to fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude “the inventor invented the claimed invention”.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Applicant has amended claim 1 to recite that the subject has a recessive mutation in the ANO5 gene. It is noted that this is not limited to a homozygous mutation and thus, the claim encompasses treatment of heterozygotes, which would have a wildtype appearance.
Applicant’s remarks have been fully considered and are not persuasive. Applicant discusses the phenotype of the Ano5-/- mouse and that Example 3 shows that administration of rAAVrh.74.MHCK.huANO5.FLAG led to partial restoration of membrane sealing and, therefore, the specification describes treatment of muscular dystrophy and muscle wasting associated with an ANO5 mutation. Applicant asserts that based on proof of principle experiments and the description in the specification, the skilled artisan would understand that a subject that has a recessive mutation in the ANO5 gene and related muscle wasting can be treated by restoration of ANO5 activity. Applicant asserts the skilled artisan would understand the genus of proteins that exhibit ANO5 activity because the specification teaches how to assess the various symptoms exhibited by the mutant mouse. In response, written description is met if enough species within a genus are described or enough detailed characterization is provided, such that one could readily envision other members of the genus. The only ANO5 protein shown to partially restore membrane resealing is that set forth be the sequence of SEQ ID NO:2. Applicant has not provided any structural/functional relationship of ANO5 such that one would know what variations can be made while retaining function.
Claims 2-8 and 10-14 remain 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 the claimed method wherein the treatment is membrane repair in a subject lacking ANO5 activity, wherein the route of administration is intramuscular, wherein the rAAV comprises the MHCK7 promoter operably linked to the nucleic acid sequence set forth in SEQ ID NO:1 or a nucleic acid sequence encoding the amino acid sequence set forth in SEQ ID NO:2, does not reasonably provide enablement for the full breadth of the claims 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/or use the invention commensurate in scope with these claims.
The teaching of the specification and the presence of working examples:
The specification in example 1 describes generation of an Ano5-/- mouse model. Example 2 describes clinical and histopathological evaluation of the Ano5-/- mouse. Example 3 teaches that Ano5 facilitates membrane repair in Ano5-/- muscles (see [00126]). To test whether the defect in membrane repair was directly related to ANO5 expression, the human ANO5 cDNA was expressed using adeno-associated virus (AAV) in the Ano5-/- muscles (Fig. 4b,c). The human ANO5 cDNA (SEQ ID NO: 1) was cloned into an AAV2 ITR plasmid using Not1 restriction sites between the MHCK7 promoter and a polyadenylation signal. The rAAV vector was delivered through intramuscular injection to mouse muscle. Four-five week old Ano5-/- mice were treated by intramuscular injection of 1x1011 vg rAAVrh.74.MHCK7.huANO5.FLAG into the tibialis anterior muscle (TA; n=4) or flexor digitorum brevis (FDB; n=4) muscles. TA muscles were harvested 4 weeks post injection and subjected to laser induced injury [00126]. AAV.ANO5 partially restored membrane resealing in Ano5-/- muscle (Fig. 5a,b,c).
Example 4 describes impaired muscle regeneration in Ano5 KO mice. Investigation of whether muscle regeneration was also defective in Ano5-/- mice was carried out by examining the ability of the muscle to recover from injury produced by cardiotoxin injection (Fig. 5d). Muscles of WT mice were able to regenerate while, in Ano5-/- mice, there was an extensive delay in regeneration and longstanding necrosis. After 3 months, the mean fiber diameter of Ano5-/- muscle remained significantly reduced compared to WT and many fibers exhibited central nuclei (Fig. 5d,e). There was no treatment with rAAVrh.74.MHCK7.huANO5.FLAG.
In summary, the specification teaches in example 3 that intramuscular injection of the AAAVrh.MHCK7.hANO5 (SEQ ID NO:1).FLAG vector into Ano5-/- mice partially restored membrane resealing in Ano5-/- mice (Fig. 5a,b,c). In example 4 the specification teaches there was an extensive delay in regeneration and longstanding necrosis in 8 week old Ano5-/- mice cardiotoxin-induced muscle injury vs age matched control mice. After 3 months, the mean fiber diameter of Ano5-/- muscle remained significantly reduced compared to WT and many fibers exhibited central nuclei (Fig. 5d,e). However, this example does not discuss any treatment. The Specification does not teach that administration of the rAAV-encoded ANO5 rescued the delay in regeneration.
The state of prior art and the level of predictability in the art:
The claims read on gene therapy by using a rAAV vector with SEQ ID NO: 1 nucleic acid by any route of administration for treating chronic muscle wasting or to regenerate muscle in any subject in need thereof. The state of the art for gene therapy for treating muscle was unpredictable at the time of the invention.
Mahmood (Molecular Medicine Reports, 9: 1515-1532, 2014; IDS) notes that in LGMD2L patients harboring autosomal recessive mutations in the Ano5 gene, there is loss of function of Calcium-activated chloride channel function and membrane resealing mechanism, resulting in Anoctinopathies. Mahmood teaches that there are different types of muscular dystrophies that are cause by mutation of distinct genes. ANO5 is the gene responsible for LGMD2L. Xu (Skeletal Muscle (2015) 5:43) also notes genetic disruption of Ano5 gene in mice does not recapitulate human Ano5-deficient muscular dystrophy. Xu notes that genetic ablation of Ano5 in C57BL/6J mice does not cause overt pathology in skeletal and cardiac muscles, but Ano5 deficiency may lead to altered lipid metabolism and inflammation signaling (abstract). Thiruvengadam (Journal of Neuromuscular Diseases 8 (2021) S243–S255; IDS) notes that Mutations in the Anoctamin 5 (Ano5) gene that result in the lack of expression or function of ANO5 protein, cause Limb Girdle Muscular Dystrophy (LGMD) 2L/R12, and Miyoshi Muscular Dystrophy (MMD3). However, the dystrophic phenotype observed in patient muscles is not uniformly recapitulated by ANO5 knockout in animal models of LGMD2L (abstract). Thus, the art fails to support that the mutation of ANO5 that is linked to human LGMD leads to muscular dystrophy in mice.
Regarding intravenous injection Mingozzi (2011, Nature Reviews Genetics. 12:341-355; IDS) notes human studies with AAV indicate that vector can be found in body fluids (such as serum, urine and semen) for several weeks after systemic vector administration, but thereafter disappears (see p 2, Box 1). Mingozzi notes there were concerns over the transduction of germline cells with AAV vectors following systemic vector administration in humans (see p 2, Box 1). Additionally, intravenous delivery is systemic and not targeted to the site of damage. The specification teaches repair of damaged muscle cell membrane by intramuscular administration.
Regarding treatment effect, neither the Specification nor the post-filing Griffin publication (Human Molecular Genetics, Volume 25, Issue 10, 15 May 2016, Pages 1900–1911; IDS) teach any treatment effect other than muscle cell membrane repair. The Specification and the art fails to correlate the resealing of cell membranes to any other effect that would be considered treatment of chronic muscle wasting or muscle regeneration (such as performance on the treadmill test). This is also supported by the Christiansen review (2022, Genes and Diseases, 9:1506-1520). While membrane resealing was observed, there is no mention of any other treatment effect of the claimed method. Additionally, while the mutant mouse does undergo physical testing to assess muscular phenotypes, the only treatment of those phenotypes is shown to be by administration of antioxidants. The specification fails to provide any guidance for any treatment effect other than membrane repair via intramuscular administration. It is noted that the specification does not provide a definition for “treatment”.
Regarding a nucleotide that hybridizes under stringent condition to the nucleotide sequence of SEQ ID NO: 1, for example in terms of the structural requirements of the nucleic acid molecules, the claims 2-3 recite an arbitrary structural relationship between the claimed nucleic acid sequence(s) and the single disclosed species of nucleotide sequence and amino acid sequence, respectively, based upon hybridization of nucleic acid. Hybridization of two nucleic acids, even under high stringency conditions, requires only that the two nucleic acids share between 25 and 50 nucleotides in common. (Kennell, Progr Nucleic Acid Res. Mol. Biol. 11: 259-301, 1971, at the paragraph bridging pages 260-261; IDS). Such a sequence encodes only 8-16 amino acids. Consequently, the claims embrace polypeptides that could share as few as 8-16 contiguous amino acids in common out of the 293 amino acids of SEQ ID NO: 2. Conversely, a nucleotide sequence that differs in every wobble base from SEQ ID NO: 1, for example, would encode SEQ ID NO: 1, but would not detectably hybridize to SEQ ID NO: 1 under any conditions.
The specification fails to provide any guidance at all for treating any subject for chronic muscle wasting or to regenerate muscle by intravenous injection of any recombinant AAV vector comprising the nucleic acid sequence of SEQ ID NO:1, or a nucleotide that hybridizes under stringent condition to the nucleotide sequence of SEQ ID NO: 1 and/or c) a polynucleotide sequence encoding the amino acid sequence of SEQ ID NO: 2.
Thus, the specification fails to provide clear and convincing evidence in sufficient support of the broad methods for any mode of administration of a rAAV vector that lacks essential control elements (promoter that expresses in muscle, for example) to express the nucleic acid of SEQ ID NO: 1, variants and fragments in a manner that will lead to treatment of muscle wasting or regenerate muscle.
Thus, a skilled artisan would have to perform undue experimentation to implement the invention. It would have required undue experimentation for one of skill in the art to make and use the invention as claimed without a reasonable expectation of success.
While the specification teaches intramuscular injection of the AAAVrh.MHCK7.hANO5 (SEQ ID NO:1).FLAG vector into Ano5-/- mice partially restored membrane resealing in Ano5-/- mice the art teaches the Ano5-/- animal model fails to model any particular disease. Thus, the intramuscular injection of the AAAVrh.MHCK7.hANO5 (SEQ ID NO:1).FLAG vector into Ano5-/- mice partially restored membrane resealing in Ano5-/- mice cannot be extrapolated to treat chronic muscle wasting or regenerate muscle in any subject as claimed. Thus, a skilled artisan needs to perform undue experimentation to extrapolate the Ano5-/- mice partially restored membrane resealing in Ano5-/- mice into any subject.
Applicant argues that a claim is enabled if it can be practiced without undue experimentation and that one of skill in the art would know how to determine is a protein has ANO5 activity. This argument relates to written description. The issue of enablement is whether muscle is regenerated by administration of ANO5. As set forth above, the specification only supports partial membrane resealing and does not show that this effect leads to improvements in other disease phenotypes such as increased serum creatine kinase levels, variable weakness among muscles, altered muscle fiber diameter and exercise intolerance. There is no evidence that the partial restoration of membrane resealing led to an alteration in any other symptom exhibited in the mice. Applicant asserts that the skilled artisan would understand that the intramuscular delivery of the ANO5 construct is exemplary a non-limiting and the specification envisions and describes and enables additional methods. Mere mentioning alternate routes of administration is not enabling. As set forth above, there are considerations to be made for various modes of administration such as degradation and the trafficking to the desired cells. The specification supports direct delivery into the target muscle. Applicant did not address the basis of the rejection that the art does not support that the ANO5 mouse mutant does not reflect a human disease.
Conclusion
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.
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/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632