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 .
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 82-84 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 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 or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are directed to delivery of a rAAV “comprising” (open language) a nucleotide sequence selected from the group consisting of:
(a) a nucleotide sequence of any length (i.e. 4 nt or 400 nt or 1400 nt) comprising at least 80% identity to the sequence set forth in SEQ ID NO: 1;
(b) a nucleotide sequence of any length that is complementary to the nucleotide sequence comprising at least 80% identity to the sequence set forth SEQ ID NO: 1;
(c) a nucleotide sequence of any length (i.e. 10000 nt) comprising the sequence set forth in SEQ ID NO: 1;and
(d) a nucleotide sequence of any length complementary to the nucleotide sequence comprising the sequence set forth in SEQ ID NO: 1.
The specification does not adequately describe the structure required for the function. The specification does not disclose any species other than SEQ ID NO: 1 that have the required function. The species are not representative of the entire claimed genus.
The genus encompasses an enormous possible genus of nucleotide sequences of varying lengths and overall specificities when considering the entire length of each sequence that would not likely function as claimed. Without further description of the structure required for the function, one would not be able to readily recognize which nucleotide sequence species within the genus would have the required function; and would therefore not be able to recognize that applicant was in possession of the entire claimed genus at the time of filing.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The claims are rejected under the written description requirement for failing to disclose adequate species to represent the claimed genus, the genus being nucleotide sequences within the instantly claimed genus that have the structure to achieve the required function.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
To have the required function, it appears that the nucleotide sequence would need to code for the full-length protein and comprise continuous coding sequence long enough to specify all of the protein’s amino acids, plus start and stop signals. However, the claims encompass a large genus of fragments of varying lengths and sequences with large extraneous non-specific regions.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for nucleotide sequences within the instant enormous genus that function as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Response to Arguments
Applicant argues that the specification, at least at paragraphs 70-73, discloses the complete 1753 nucleotide sequence of SEQ ID NO: 1, providing the precise structure of the U7-ACCA nucleotide sequence. This complete sequence disclosure demonstrates that Applicant was in possession of the claimed subject matter at the time of filing.
Contrary to applicant’s argument, the rejection sets forth that the specification does describe the full length sequence of SEQ ID NO: 1, but this is not commensurate in scope with the claim language; and is not representative of the entire claimed genus.
Applicant argues that the specification, at least at paragraph 67, describes that 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 provides one of ordinary skill in the art with a clear understanding of the functional elements within SEQ ID NO: 1.
However, the enormous genus of possible fragments of any length as claimed encompass a large genus of sequences that would not have these required structures.
Applicant argues that the specification provides multiple working examples demonstrating the function of SEQ ID NO: 1. Example results show that one-time tail vein injection of scAAV9.U7 into 2-month old Dup2 mice results in highly efficient exon skipping, translation of both full-length and IRES-driven dystrophin proteins, and correction of clinical, histopathological, and physiologic markers of disease.
These results are dependent upon the structure of SEQ ID NO: 1, although the claims encompass an enormous genus of possible fragments of any length that encompass a large genus of sequences that would not have the required structures for the required function.
Applicant argues that because of the detailed support as noted above, one of ordinary skill in the art would recognize that variants within 80% identity to SEQ ID NO: 1 that maintain the antisense targeting sequences would function similarly.
Contrary to applicant’s argument, without further description of the structure required for the function, one would not be able to readily envision which species of the variants of what length and specificity to the target would in fact function as required. The claimed genus encompasses an enormous genus of possible fragments of any length that encompass a large genus of sequences that would not have these required structures.
Applicant’s arguments that the critical functional elements are the antisense sequences targeting the splice acceptor and splice donor sites, and variants maintaining these targeting sequences would be expected to achieve the same exon-skipping function assume that these structures would be present in the sequence, although the claims encompass sequences that omit these required elements.
Applicant argues that the claims recite "a nucleotide sequence comprising at least 80% identity to the sequence set forth in SEQ ID NO: 1" as recited in claim 8(a). Given that SEQ ID NO: 1 is 1753 nucleotides, an 80% identity threshold permits approximately 350 nucleotide variations while maintaining the core antisense targeting sequences essential for exon 2 skipping function. One of ordinary skill in the art would understand that such variants maintaining the functional antisense elements would achieve the claimed therapeutic effect.
Again, the claims encompass sequences that do not maintain the elements argued by applicant. Additionally, applicant’s argument and calculation are 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 (i.e. 4 nt) that meets the instant limitation of comprising at least 80% identity to SEQ ID NO: 1; a sequence of 10,000 nucleotides comprising SEQ ID NO: 1; or a sequence of any length (4 nt) that is complementary to the sequence comprising SEQ ID NO: 1. This is a genus that applicant was not in possession of at the time of filing.
Claims 8-12, 20-25, 27, 29-31, and 82-84 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 breadth of possible sequences. 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 breadth of possible sequences.
The instant specification discloses insertion of the entirety of instant SEQ ID NO: 1 (1753 nt) into an AAV 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 via delivery of the instant breadth of possible sequences.
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, 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 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
Applicant argues that the Examiner's assertion that the claims encompass treatment of "any muscular dystrophy" is addressed by the specification's disclosure that the methods are directed to patients with 5' mutations of the DMD gene, as recited in the pending claims, as amended. It is noted that the claims are not limited to what is disclosed in the specification and the previously pending claims were in fact directed to the treatment of any muscular dystrophy, which is not commensurate in scope with the specification.
Applicant argues that duplications of one or more exons cause up to 11% of all DMD cases, and duplications of exon 2 are the most common, accounting for 10% of all duplications. Targeting of exon 2 duplication mutations provides a very wide therapeutic window. For example, skipping of a single copy results in a full-length wild-type dystrophin, and skipping of both copies results in alternate translational initiation from a highly functional internal ribosome entry site (IRES) within exon 5. The specification further demonstrates that the methods are enabled for patients with mutations within exons 1-4. Mutations in exons 1 to 4 represent 5-6% of the DMD patient population. Because no animal models are available to test this hypothesis, patient-derived fibroblasts that were transdifferentiated into myoblasts (FibroMyoD) were used to evaluate exon skipping and dystrophin expression following treatment with scAAV1.U7-ACCA, with or without PDN. The five cell lines each carried different mutations. Three cell lines have nonsense mutations within exons 1-3; one cell line carries a splice site mutation in the -1 position relative to exon 3 that results in an in-frame exon 3-deleted transcript; and one cell line carries an in-frame duplication of exons 3-4. After treatment, all cell lines with nonsense mutations displayed a transcript corresponding to nearly 100% exon 2 skipping.
However, the instant claims encompass delivery of an enormous possible genus of sequences of any length (i.e. 4nt) that are 80% identical to instant SEQ ID NO: 1 and do not have the structural requirements to result in targeting of exons 1, 2, 3, or 4 mutations.
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 argues that the disclosure provides antisense targeting sequences embedded into a modified U7 small nuclear RNA (U7snRNA), which becomes a part of a small nuclear ribosomal protein complex (snRNP) that protects the antisense sequence from degradation and allows for accumulation in the nucleus where splicing occurs. The U7snRNA, which contains internal promoters allowing for continuous transcription of the downstream antisense sequences, in some aspects, is encapsulated into an AAV for widespread tissue delivery. The specification explicitly contemplates the claimed sequence identity variants.
Again, applicant is arguing limitations that are not recited in the claims. The specification in fact does not contemplate the genus of variants encompassed by the claims. 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 (i.e. 4 nt) that meets the instant limitation of comprising at least 80% identity to SEQ ID NO: 1; a sequence of 10,000 nucleotides comprising SEQ ID NO: 1; or a sequence of any length (4 nt) that is complementary to the sequence comprising SEQ ID NO: 1.
The specification argues that the disclosure utilizes AAV to deliver inhibitory U7snRNA to deliver a DMD antisense sequence, e.g., U7-ACCA, which binds to key exon definition elements in the pre- mRNA, inhibiting the recognition of a specific exon by the spliceosome, leading to exclusion of the target exon from the mature RNA, resulting in the expression of dystrophin. The critical functional elements are the antisense sequences targeting the splice acceptor and splice donor sites, and variants maintaining these targeting sequences would be expected to achieve the same exon-skipping function.
Applicant is arguing limitations that are not claimed. The claims are not limited to the specific vector argued by applicant and the entire genus of variants 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. 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.
Applicant argues that the specification, at Example 10, provides results from an intramuscular dose escalation study with scAAV9.U7-ACCA. Five single doses of the scAAV9.U7.ACCA test article at half-log increments: 2.0x10^10 vg, 5.6x10^10 vg, 2.0x10^11 vg, 5.6x10^11 vg and 2.0x10^12 vg were administered in the tibialis anterior (TA) muscle.
Again, the claims are not limited to delivery of scAAV9.U7-ACCA.
Applicant argues that thus, the specification provides sufficient guidance through multiple working examples demonstrating that systemic delivery of scAAV9.U7-ACCA containing SEQ ID NO: 1 achieves exon 2 skipping and dystrophin restoration in both mouse models and human subjects. However, the claims are not directed to systemic delivery of scAAV9.U7-ACCA containing SEQ ID NO: 1 achieving exon 2 skipping and dystrophin restoration. 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 any rAAV comprising any sequence of the enormous claimed breadth.
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) 8-10, 20-22, 24, 25, 27, 29, 30, and 82-84 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Flanigan et al. (WO 2014/172669 A1).
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 and 24).
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 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.
The sequence of the genome insert taught in Figure 9 of Flanigan comprises instant SEQ ID NO: 1 (starting at nucleotide 114) (instant claim 8).
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 claims 30 and 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 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 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, the claims are anticipated by Flanigan et al.
Response to Arguments
Applicant’s Declaration of Kevin Flanigan under 37 C.F.R. 1.130(A) has overcome the rejection under 35 USC 102(a)(2). However, the claims remain rejected under 35 USC 102(a)(1).
Applicant argues that Flanigan does not teach the dosage recited in claim 8. For at least this reason, Flanigan does not teach each and every element of the pending claims, and thus does not anticipate the claimed subject matter.
Contrary to applicant’s argument, 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).
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 82-84 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).
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 and 24).
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 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.
The sequence of the genome insert taught in Figure 9 of Flanigan comprises instant SEQ ID NO: 1 (starting at nucleotide 114) (instant claim 8).
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 claims 30 and 31).
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).
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 claims 11 and 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 consider to be a matter of design choice depending upon the considerations taught by Flanigan et al.
Response to Arguments
Applicant’s Declaration of Kevin Flanigan under 37 C.F.R. 1.130(A) has overcome the rejection under 35 USC 102(a)(2). However, the claims remain rejected under 35 USC 102(a)(1) and the instant rejection under 35 USC 103.
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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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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