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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/3/26 has been entered.
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 8, 12, 20-25, 27, 29-31, and 82-88 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 systemic delivery of scAAV9.U7-ACCA (AAV with full length SEQ ID NO: 1) and a resultant mediation of exon 2 skipping and dystrophin restoration in muscles, does not reasonably provide enablement for a method for treating, for absolute prevention, or ameliorating any muscular dystrophy with any 5’ mutation of the DMD gene via delivery of the instant construct. 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.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(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.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The instant claims are directed to a method for treating, for absolute prevention, or ameliorating any muscular dystrophy via delivery of the instant construct.
The instant specification discloses insertion of the entirety of instant SEQ ID NO: 1 (1753 nt) into an AAV9 backbone [0070] followed by systemic delivery of scAAV9.U7-ACCA and a resultant mediation of exon 2 skipping and dystrophin restoration in muscles of Dup2 adult mice. To determine whether systemic delivery of scAAV9.U7-ACCA mediates efficient exon skipping and dystrophin expression, the scAAV9.U7-ACCA vector was injected into 2- month-old Dup2 mice via tail vein injection at 7.6e13 vg/kg (Example 2).
The example of the specification is not commensurate in scope with the claims and is not enabling for a method for treating, or absolute prevention, or ameliorating any muscular dystrophy in a subject with any possible 5’ mutation of the DMD gene via delivery via any means of the instant construct.
Additionally, the example was specific to a laboratory model that carries a duplication of exon 2 in the gene for dystrophin, which is not true for all muscular dystrophies as claimed. The example is not enabling for any mode of delivery with each of the predictable outcomes.
With regards to DMD, a single species within the instant genus of muscular dystrophies with a 5’ mutation in the DMD gene, Sattenapalli et al. (Iran J Child Neurol. Winter 2023; 17 (1): 29-37) teach that Duchene Muscular dystrophy (DMD) is the common X-linked heterogenous progressive muscular dystrophy characterized by mutations in the DMD gene. The frequency of dystrophin gene mutations is varied in different DMD population (page 29).
Sattenapalli et al. teach that mutation spectrum was studied on 250 DMD patients, of which 63% exon deletion pattern were reported. 16% deletions were detected in proximal hot region (exons 3-28). The duplications were found 21% in the proximal hotspot largest region (exon 3-25). 16% of the patients reported single deletion (45 exon), 10.7% reported deletions of exon 44. Point mutations detected in 6%, small mutations were detected in 1.2%, non-sense mutations were detected in 2% of study population respectively. Missense Mutations were detected in 0.8% of study (page 29).
Therefore, Sattenapalli et al. is evidence that the frequency and type of mutations differ even in DMD depending upon the patient and population.
Sattenapalli et al. teaches: A plot was constructed between the total number of study patients and specific duplication affected ((Figure 2). A total of 21 patients have shown duplication between 3 and 25 exons (21%). There are 12 patients (19%) who reportedly shown duplications in the exons between 45-55, 15 patients (23.8%) reported duplications between exon 8 to exon 9, 10 patients (15.8%) reported duplications between exon 60 to exon 66, 4 patients (6.3%) reported duplications on exon 63 and only one patient reported duplications on exon 66 (1.6%) (Fig 2). On the other hand, Exon deletion of 3 to 28 is identified in 17 patients (16.6%), 4 patients (3.9%) reported exon deletions between 53 and 60, 3 patients (2.9%) reported deletions in the region of 61 and 79, 32 patients (31.3%) reported exon deletions between 40 and 45, 42 patients (41.1%) reported exon deletions in the hotspot region of 45 and 52 (Figure 3). Deletions were found in 2 patients (1.9%) each in the regions of 29 to 35 and 35 to 40 respectively. These were reflected in Figure 3 with a plot between exon deletion pattern and total number of study patients.
Therefore, delivery of the instant genus of nucleotide sequences of any length that comprises sequences that are at least 95% identical to SEQ ID NO: 1 that do not encode the entire protein via any means of delivery would not likely result in the predictable treatment, absolute prevention, or amelioration of any muscular dystrophy in a subject with any 5’ mutation of the DMD gene.
With regards to the genus of possible sequences, it appears that skipping of exon 2 is required in order to achieve activation of the exon 5 IRES and subsequent production of an active dystrophin protein. Without successful delivery to the target of a sequence that would result in skipping exon 2, the method would not result in each of the recited outcomes in a predictable manner without undue experimentation.
The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of treating, absolute preventing, or ameliorating any muscular dystrophy encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of
the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed
invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27
USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of any sequence within the instantly recited genus in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful treating, absolute preventing, or ameliorating any muscular dystrophy. To practice the claimed invention, one of skill in the art would have to de novo determine; the specificity of the actual nucleotide sequence, the ability of the nucleotide sequence to encode the required product, the stability of the nucleotide sequence in vivo, delivery of the nucleotide sequence to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Response to Arguments
It is noted that the specification is not enabling for treatment of any muscular dystrophy wherein the subject has any possible 5’ mutation of the DMD gene as recited in the instant preamble.
Applicant argues that the specification explains the structural basis for the function of SEQ ID NO: 1. The vector contains four copies of the U7snRNA in a self-complementary genome, with two copies targeting the splice acceptor site (sequence A) and two copies targeting the splice donor site (sequence C), encapsulated in AAV9 (scAAV9.U7ACCA). This structural description enables one of ordinary skill in the art to understand which features are essential for function.
Applicant is arguing limitations that are not claimed. The claims are not limited to the specific vector argued by applicant. Applicant’s arguments appear to be based upon a sequence that is the same length as SEQ ID NO: 1, although the claims are directed to a sequence of any length that meets the instant limitation of comprising a sequence that is at least 95% identical to SEQ ID NO: 1 (a sequence of 10,000 nucleotides comprising SEQ ID NO: 1 comprises a sequence comprising at least 95% identical to SEQ ID NO: 1).
The claims are not limited to the specific vector argued by applicant and the entire genus of variants comprising sequences that are at least 95% identical would certainly not be expected to achieve the same exon-skipping function because they would not have the required structural elements to function as required. For example, the specification has not demonstrated that the presence of any 1665.35 nucleotides out of the 1753 nucleotides of SEQ ID NO: 1 would result in the recited functions.
Applicant’s arguments regarding the experimentation of the specification are directed to a specific vector consisting of the entire sequence of SEQ ID NO: 1.
The claims are directed to a method of treating or absolute prevention or ameliorating a muscular dystrophy with any 5’mutation of the DMD gene comprising administering a construct of the instant genus via any means.
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 (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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 8, 12, 20-25, 27, 29-31, and 82-88 is/are rejected under 35 U.S.C. 103 as being obvious over Flanigan et al. (WO 2014/172669 A1), in view of McNally et al. (US 2014/0037637 A1), Odermatt et al. (Molecular Therapy vol. 24 no. 10, 1797–1805, 2016), and Mendell et al. (New England Journal of Medicine 377:1713–1722, 2017).
The Flanigan et al. and McNally et al. references are of record.
Flanigan teaches a method of delivering a recombinant adeno-associated virus (rAAV) comprising polynucleotides for treating Duchenne Muscular Dystrophy resulting from the duplication of DMD exon 2. The invention provides rAAV products and methods of using the rAAV in the treatment of Duchenne Muscular Dystrophy (abstract, [0002]) (instant claims 8, 24, and 88).
Flanigan teaches: recombinant AAV constructing insert DNA, SEQ ID 2, which is 2052 nucleotides in length and comprises instant SEQ ID NO: 1 at nucleotides 115-1867 and therefore comprises a sequence that is 100% identical to instant SEQ ID NO: 1(Example 3, SEQ ID NO: 2) (instant claims 8 and 85-87).
Flanigan teaches: [0005] One form of MD is Duchenne Muscular Dystrophy (DMD). It is the most common severe childhood form of muscular dystrophy affecting 1 in 5000 newborn males. DMD is caused by mutations in the DMD gene leading to absence of dystrophin protein (427 KDa) in skeletal and cardiac muscles, as well as GI tract and retina. Dystrophin not only protects the sarcolemma from eccentric contractions, but also anchors a number of signaling proteins in close proximity to sarcolemma. Many clinical cases of DMD are linked to deletion mutations in the DMD gene.
Flanigan teaches: [0051] Mice carrying a duplication of exon 2 within the Dmd locus were developed. The exon 2 duplication mutation is the most common human duplication mutation and results in relatively severe DMD. Flanigan et al. teaches targeting the exon2 duplication mutation in the 5’ region of DMD gene.
Flanigan teaches: [0031] In embodiments of the invention, an effective dose is a dose that alleviates (eliminates or reduces) at least one symptom associated with DMD being treated, that slows or prevents progression to DMD, that slows or prevents progression of a disorder/disease state, that diminishes the extent of disease, that results in remission (partial or total) of disease, and/or that prolongs survival (instant claim 8).
Flanigan teaches delivery of a U7snRNA via the AAV vector to target exon 2 of the DMD gene [0013]. Flanigan tech a method of ameliorating DMD in a patient comprising administering a rAAV to the patient, wherein the genome of the rAAV comprises an exon 2-targeted U7snRNA polynucleotide construct [0015].
Flanigan teaches at Example 4 that the intramuscular delivery of U7-ACCA by AAV1 results in significant N-truncated dystrophin expression in Dup2 mice. Flanigan teaches: [0068] A rAAV comprising the genome insert of Figure 9 was produced by the methods described in Example 3. The AAV.1U7-ACCA was then administered to Dup2 mice via intramuscular injection.
Flanigan et al. teaches that four copies of the U7 construct were included in a vector genome [0065].
Flanigan et al. teaches the U7_ACCA vector as containing: U7Along-U7C-U7C-U7Along, which is four exon-2 targeted U7 snRNA polynucleotide constructs, with two copies of U7A long and two copies of U7C. U7Along is antisense targeting the exon 2 splice acceptor region and U7C is antisense targeting the exon 2 splice donor region ([0020][0021][0040]).
The sequence of the genome insert taught in Figure 9 of Flanigan comprises instant SEQ ID NO: 1 and therefore comprises a sequence 100% identical to instant SEQ ID NO: 1 (starting at nucleotide 114) (instant claims 8 and 85-87).
Flanigan teaches: [0069] RT-PCR performed on DMD mRNA 4 weeks after TA intramuscular injection of 5el lvg AAV.1U7-ACCA showed nearly complete skipping of both copies of exon 2 in Dup2 animals [Figure 12(a)].
Flanigan teaches that intramuscular delivery of U7-ACCA by AAV1 results in significant N-truncated dystrophin expression in Dup2 mice.
With regards to selection of an AAV serotype, Flanigan teaches: [0008] There are multiple serotypes of AAV. The nucleotide sequences of the genomes of the AAV serotypes are known. For example, the complete genome of AAV-1, AAV- 2, AAV- 3, AAV-4, AAV-5, AAV-6, AAV-7, AAV-8, AAV-9, AAV-10, and AAV-11 are provided in GenBank Accession Nos (instant claims 82 and 83).
Flanigan teaches: [0020] In some embodiments of the foregoing methods of the invention, the virus genome is a self-complementary genome (instant claim 84).
Flanigan teaches: [0033] Combination therapies are also contemplated by the invention. Combination as used herein includes simultaneous treatment or sequential treatments. Combinations of methods of the invention with standard medical treatments (e.g., corticosteroids and/or immunosuppressive drugs) are specifically contemplated, as are combinations with other therapies such as those mentioned in the Background section above (instant claim 30).
Although Flanigan teaches incorporation of a combination therapy, more specifically corticosteroids and/or immunosuppressive drugs, Flanigan does not specifically teach incorporation of a glucocorticoid.
However, it would have been obvious for the combination therapy agent to be a glucocorticoid because McNally et al. teach that glucocorticoid steroids are used to slow progression in DMD [0005]. Therefore, this would have been an obvious selection to combine with another treatment to treat the same disease state with a reasonable expectation of success (instant claim 31).
It is noted that instant claims 25, 27, and 29 recite outcomes rather than method steps and the outcomes would necessarily flow from the recited method steps if the method is enabled. Recitation of “as measured by” is not a clear step of requiring a specific test be performed. However, Flanigan teaches that the improvement in stability strength is determined by techniques known in the art such as the 6-minute walk test (6MWT) or timed stair climb [0017] (instant claim 29).
Flanigan teaches: [0032] Administration of an effective dose of the compositions may be by routes standard in the art including, but not limited to, intramuscular, parenteral, intravenous, oral, buccal, nasal, pulmonary, intracranial, intraosseous, intraocular, rectal, or vaginal. Route(s) of administration and serotype(s) of AAV components of rAAV (in particular, the AAV ITRs and capsid protein) of the invention may be chosen and/or matched by those skilled in the art taking into account the infection and/or disease state being treated and the target cells/tissue (s). In some embodiments, the route of administration is intramuscular. In some embodiments, the route of administration is intravenous (instant claims 20 and 22). Flanigan teaches intramuscular and intravenous injection (instant claim 21). It is noted that intravenous is a type of infusion (instant claim 23).
Flanigan does not teach that the infusion is over approximately one hour. However, Flanigan teaches that routes of delivery may be chosen and/or matched by those skilled in the art taking into account the infection and/or disease state being treated and the target cells/tissue(s). Given that Flanigan teaches infusion, it would have been obvious as a matter of design choice and well within the technical grasp of one of ordinary skill in the art to perform the infusion for approximately one hour (instant claim 23).
Additionally, Mendell teaches systemic treatment of another inherited neuromuscular disorder using a recombinant self-complementary AAV9 vector. Specifically, Mendell administered scAAV9 carrying a therapeutic SMN transgene to patients with spinal muscular atrophy by a single intravenous infusion. Mendell expressly teaches that the AAV9 vector was diluted in normal saline and infused intravenously over a period of approximately 60 minutes. Mendell further demonstrated successful systemic administration of substantial vector doses by this approximately one-hour infusion procedure.
Flanigan teaches that rAAV dosage can be about 1x1010 vg/kg (instant claim 8), 1x1011 vg/kg (instant claim 9), or 1x1013 vg/kg (instant claim 10) (page 9).
Flanigan does not teach that the dose is about 2x1013 vg/kg to about 4x1013 vg/kg; or about 3x1013 vg/kg (instant claim 12). However, this is a very wide dosage range and Flanigan teaches: [0030] Titers of rAAV to be administered in methods of the invention will vary depending, for example, on the particular rAAV, the mode of administration, the treatment goal, the individual, and the cell type(s) being targeted, and may be determined by methods standard in the art.
Therefore, dosage is considered to be a matter of design choice depending upon the considerations taught by Flanigan et al.
Additionally, Odermatt teaches therapeutic administration of a self-complementary AAV9 vector comprising four modified U7 snRNA expression cassettes. Specifically, Odermatt constructed an scAAV9 vector containing four tandem copies of a therapeutic U7 snRNA cassette (“scAAV9 4xsU7”) and administered different doses of the vector to an animal model of a neuromuscular disease. Odermatt demonstrated that therapeutic efficacy depended upon vector dose and expressly administered the four-U7 scAAV9 vector at doses including approximately 1.75 × 10^13 vg/kg, 3.21 × 10^13 vg/kg, 4.34 × 10^13 vg/kg, and higher doses. In particular, the dose of 3.21 × 10^13 vg/kg expressly taught by Odermatt falls within the presently claimed range of about 2 × 10^13 vg/kg to about 4 × 10^13 vg/kg.
Odermatt further teaches that administration of the four-U7-cassette AAV vector produced a dose-dependent therapeutic effect. Thus, the art recognized vector dose as a result-effective variable for therapeutic delivery of multiple U7 snRNA cassettes by recombinant AAV.
It would have been obvious to one of ordinary skill in the art to administer the rAAV U7-ACCA vector of Flanigan et al. at a dose within the range taught by Odermatt, including approximately 3.21 × 10^13 vg/kg, and to administer that dose systemically by intravenous infusion over approximately one hour as taught by Mendell.
A person of ordinary skill would have had reason to apply Mendell’s intravenous infusion procedure to the method of Flanigan et al. because both concern systemic rAAV treatment of inherited neuromuscular diseases. Intravenous administration was a known means of obtaining widespread systemic exposure to recombinant AAV vectors and is taught by Flanigan et al.
Mendell provides direct human clinical evidence that an scAAV9 vector could be administered systemically by intravenous infusion over approximately 60 minutes. Thus, the skilled artisan seeking to systemically deliver the vector of Flanigan et al. would have had reason to employ the known approximately one-hour intravenous AAV infusion procedure taught by Mendell.
The use of an approximately one-hour infusion also would have represented a predictable selection of a known administration technique rather than a modification of the therapeutic mechanism of the vector of Flanigan et al. The infusion duration concerns how the predetermined vector dose is introduced into the systemic circulation; it does not alter the U7-ACCA sequence, its exon-2 targets, or its mechanism of inducing therapeutic exon skipping.
A skilled artisan would therefore have had a reasonable expectation that the therapeutic rAAV of Flanigan et al. could likewise be administered intravenously over approximately one hour. Flanigan et al. had already established that the U7-ACCA vector produced DMD exon 2 skipping and restored dystrophin expression; Odermatt established that the four-U7-cassette AAV vector could be therapeutically administered at doses encompassing the claimed range; and Mendell established a clinically successful approximately 60-minute intravenous infusion procedure for systemic scAAV9 delivery in a neuromuscular disease.
Accordingly, it would have been obvious to one of ordinary skill in the art to administer the rAAV U7-ACCA vector taught by Flanigan et al. at a dose of about 2 × 10^13 vg/kg to about 4 × 10^13 vg/kg, including approximately 3.21 × 10^13 vg/kg as expressly exemplified by Odermatt, by systemic intravenous infusion over approximately one hour as taught by Mendell, with a reasonable expectation of providing widespread vector delivery, expression of the therapeutic U7 snRNAs, DMD exon 2 skipping, and restoration of functional dystrophin. Odermatt further teaches that administration of the four-U7-cassette AAV vector produced a dose-dependent therapeutic effect.
Response to Arguments
Applicant argues that the specification demonstrates that the minimum effective dose was calculated to be about 2.9 E13 vg/kg and therefore produces a minimum effective systemic dose for achieving dystrophin restoration.
Doses in the instantly recited range would have been obvious in view of Odermatt, as set forth above.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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