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 .
This action is in response to the papers filed on 10/03/2024. Claims 1-8 are
currently pending.
Claims 1-8 are examined on their merits to which the following grounds of
rejection are applicable. Claim 1 is independent claim.
Priority
This Application is a CON of 17/203,232 filed 03/16/2021 (PAT 12121595), 17/203,232 is a CON of 15/759,474 filed 03/12/2018 (PAT 10980897), 15/759,474 is a 371 of PCT/US16/52051 filed 09/16/2016, PCT/US16/52051 claims priority to PRO 62/301,260 filed 02/29/2016, PCT/US16/52051 claims priority to PRO 62/221,068 filed 09/20/2015, PCT/US16/52051 claims priority to PRO 62/220,107 filed 09/17/2015.
Thus, the earliest the earliest possible priority for the instant application is 09/17/2015.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/17/2025, 01/17/2025 and 03/27/2026 was filed before the mailing date of the current office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Interpretation
Claim 8 recites “the rAAV.rh74.MCK.GALGT2 comprising the GALGT2 gene cassette set out in SEQ ID NO: 2”. The examiner is interpreting this claim to mean that the rAAV.rh74.MCK.GALGT2 comprises a GALGT2 gene cassette wherein the GALGT2 gene cassette is the GALGT2 gene comprised by the amino acid sequence of SEQ ID NO: 2 which can have any percent identity to the amino acid sequence of SEQ ID NO:2. This claim interpretation is necessitated as it is unclear if the claim is reciting that the amino acid sequence of SEQ ID NO: 2 is the entire construct of rAAV.rh74.MCK.GALGT2 or is claimed to the GALTGT2 gene found within the rAAV.rh74.MCK.GALGT2 construct, therefore the examiner is interpreting the claim as stated above.
Claim Objections
Claim 1 is objected to because abbreviations such as rAAVrh74.MCK.GALGT2 should be spelled out at the first encounter in the claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
. Claims 2-8 inherit the deficiencies of claim 1 insofar as they depend on claim 1.
Claim 8 recites “the GALGT2 gene cassette set out in SEQ ID NO: 2”. It is unclear if the GALGT2 gene cassette is a component of the rAAVrh74.MCK.GALGT2, or the gene cassette is the entire rAAVrh74.MCK.GALGT2. See Claim Interpretation above. The phrase “set out in” makes it unclear how the sequence is “set out” (SEQ ID NO: 2 is the sequence or one can derive it from the sequence, hence not 100% identical). SEQ ID NO:s are placeholders for sequences and not sequences themselves. It is proper when referring to SEQ IN OD:s to refer to the nucleic/amino acid of SEQ ID NO:--.
Claim Rejections - 35 USC § 112 (a)
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.
Written Deposit Rejection
The claims are directed to a recombinant adeno-associated virus rAAVrh74.MCK.GALGT2. Since the rAAV is essential to the claimed invention it must be obtainable by a repeatable method set forth in the specification or otherwise be readily available to the public. If the rAAV is not so obtainable or available, the requirements of 35 USC § 112 may be satisfied by a deposit of the plasmid. A diagram of this vector appears in the disclosure in Figure 1, but there are unknown elements present in the diagram that are necessary in order to make the vector. It is unclear if SEQ ID NO: 2 is provided to describe the entirety of the vector as the disclosure does not clearly establish the sources of the elements and their corresponding sequences.
(a) If a deposit is made under the terms of the Budapest Treaty, then a statement, affidavit or declaration by Applicants, or a statement by an attorney of record over his or her signature and registration number, or someone empowered to make such a statement, stating that the instant invention will be irrevocably and without restriction released to the public upon the issuance of a patent, would satisfy the deposit requirement made herein.
(b) If a deposit has not been made under the Budapest Treaty, then in order to certify that the deposit meets the criteria set forth in 37 CFR 1.801 -1.809 and MPEP 2402-2411.05, Applicant may provide assurance of compliance by statement, affidavit or declaration, or by someone empowered to make the same, or by a statement by an attorney of record over his or her signature and registration number showing that:
(i) during the pendency of this application, access to the invention will be afforded to the Commissioner upon request;
(ii) all restrictions upon availability to the public will be irrevocably removed upon granting of the patent in accordance with 37 CFR § 1.808(a)(2);
(iii) the deposit will be maintained in a public depository for a period of 30 years or 5 years after the last request or for the effective life of the patent, whichever is longer;
(iv) a test of the viability of the biological material at the time of deposit (see 37 CFR § 1.807); and,
(v) the deposit will be replaced if it should ever become inviable.
Scope of Enablement
Claim 1-8 is 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:
treating Duchenne Muscular Dystrophy in a human subject in need thereof comprising administering rAAVrh74.MCK.GALGT2 wherein the route of administration is:
1) an intramuscular route and the dose of the rAAV administered is about 3x1011 vg/injection to about 5x1012 vg/injection and
2) a inter-arterial limb perfusion route and the dose of the rAAV administered is about 6x1012 vg/kg/limb to about 4.8x1013 vg/kg/limb
does not reasonably provide enablement for:
a method of treating any neuromuscular disorder in a human subject comprising the step of administering rAAVrh74.MCK.GALGT2 through systemic intravenous administration
breadth of the claim; nature of the invention
The claim is broad, encompassing treating any neuromuscular disorder in a human subject comprising the steps of administering rAAVrh74.MCK.GALGT2 through various routes of administration (intramuscular, inter-arterial limb, and systemic intravenous) and at various concentrations for each route of administration. Thus, the claims are drawn to a large genus of neuromuscular disorders and numerous routes of administration with numerous corresponding concentrations for each route of administration.
the amount of direction provided by the inventor; the existence of working examples:
However, the specification does not disclose a reduction to practice in the method of treating a neuromuscular disorder in a human subject comprising the steps of administering rAAVrh74.MCK.GALGT2 through various routes of administration (intramuscular, inter-arterial limb, and systemic intravenous) and at various concentrations for each route of administration. While the specification recites exemplary protocols which detail steps for each route of administration (intramuscular for DMD – example 2, page 23; vascular delivery by isolated limb perfusion, no mention of disorder treated – example 4, page 26; systemic vascular delivery for a mdx mouse model – example 5, page 28), there are no data of the results from the contemplated working examples of using the rAAVrh74.MCK.GALGT2 for treatment of any neuromuscular disorder, hence no indication of success in using the method. Specifically, the specification is silent about any in vivo working examples where the rAAVrh74.MCK.GALGT2 are administered via any of the disclosed routes of administration, at any of the disclosed concentrations, and for treatment of any neuromuscular disorder such that the treatment causes an improvement in any of the metrics recited in the claims.
Thus, the specification does not provide sufficient teachings for the enablement of treating any neuromuscular disorder.
the state of the prior art; the level of predictability in the art:
While use of rAAVs for gene therapy has been widely demonstrated in the art, challenges remain in achieving efficient and targeted delivery such that their associated disorders are successfully treated. For example, genetic engineering, route optimization, and immune modulation are key areas of active research to improve therapeutic outcomes and require tailoring to effectively target and treat their associated disorder, hence demonstrating unpredictability in successful use of rAAVs.
In regards to limb perfusion methods, Xu et al (Mol. Ther. Methods and Clin. Dev. 2018, pages 89-104) teaches an isolated limb perfusion method that allows broad distribution of rAAVrh74.MCK.GALGT2 to leg skeletal muscles in the rhesus macaque, which serve as models for humans. Similarly, Chicoine et al (Molecular Therapy, 2014, pages 713-724; as cited in IDS) teaches methods for isolated limb perfusion of rAAVrh74.MCK.GALGT2 in the rhesus macaque, but expression in the muscle was decreased when macaques had preexisting immunity (page 714, right col, para 2) and use as a treatment for a neuromuscular disorder was not tested. However, Flanigan et al (Molecular Therapy Advances, 2022, pages 47-60) teaches isolated limb perfusion of the rAAVrh74.MCK.GALGT2 to human subjects (abstract, page 1), thus demonstrating enablement of limb perfusion for administration of the claimed invention in human subjects.
In regards to intramuscular injection methods, Chicoine teaches intramuscular injection to the tibialis anterior muscle with rAAVrh74.MCK.GALGT2 in a rhesus macaque can permit transduction of the vector to the muscle (page 714, left col, para 2) but its use as a neuromuscular dsorder treatment was not studied. Also, Flanigan teaches that intramuscular injection can lead to the generation of a negative immune response (page 48, right col, para 1) therefore was not used in clinical trial setting, demonstrating unpredictable and detrimental outcomes using IM injection as a method of administering rAAVrh74.MCK.GALGT2 can occur.
In regards to systemic intravenous injection methods, Zygmunt et al (Mol Ther Methods Clin Dev, 2019, pages 305-319) teaches safe and high transduction of rAAVrh74.MCK.GALGT2 when intravenously delivered via tail vein of mice (abstract, page 1), however no other known studies exist using intravenous injection, hence intravenous injection remains in the pre-clinical stage of development and has not been shown to be successful in human subjects for the treatment of any neuromuscular disorder.
Thus, while the prior art highlights the administration of rAAVrh74.MCK.GALGT2 using limb perfusion and intramuscular injections in rhesus macaque models, there is little evidence in the predictability of administering rAAVrh74.MCK.GALGT2 through systemic circulation as it has only been accomplished in mouse models which do not faithfully recapitulate human systemic physiology.
the quantity of experimentation needed to make or use the invention based on the content of the disclosure:
The skilled artisan would be required to perform under levels of experimentation in order to practice the claimed invention. While the instant application discloses contemplated methods to treating mouse models to study the dose escalation using systemic vascular delivery via IV injection through the tail vein at a contemplated dose of 1.5 x1015 vg/kg to 5 x 1015 vg/kg, there is not enough information in the prior art indicating the feasibility and predictable outcomes regarding treating any neuromuscular disease using systemic intravenous administration and in a human subject. Furthermore, while the prior art discloses limb perfusion as an administration route for rAAVrh74.MCK.GALGT2 in a human subject for Duchenne muscular dystrophy, there is no indication of treatment of any other neuromuscular disorder in a human using rAAVrh74.MCK.GALGT2 through limb perfusion approaches.
Thus, the skilled artisan would be forced to identify 1) the route of administration needed to treat the particular neuromuscular disorder, 2) the dosage required to treat the particular neuromuscular disorder and, 3) determine if there is improvement in any of the recited metrics claimed in claim 7 after administration of the rAAV to the patient.
Conclusion
When all of the Wands factors are considered together, they establish a prima facie case that the specification is not enabling for the claims. The specification and state of the prior art only provide details pertaining to treating Duchenne Muscular Dystrophy in a human subject in need thereof comprising administering rAAVrh74.MCK.GALGT2 wherein the route of administration is:
1) an intramuscular route and the dose of the rAAV administered is about 3x1011 vg/injection to about 5x1012 vg/injection and
2) an inter-arterial limb perfusion route and the dose of the rAAV administered is about 6x1012 vg/kg/limb to about 4.8x1013 vg/kg/limb
While a lack of a working embodiment showing relevant data to support the methods cannot be a sole factor in determining enablement, the lack of any working examples, in light of the unpredictable nature of the art and the minimal direction applicants present for systemic intravenous administration, provides additional weight to the scope of enablement in consideration of the Wands factors as a whole. Thus, one of ordinary skill in the art would not have had a reasonable expectation of success in making or using the claimed invention beyond the scope of the disclosure and current state of the art.
Claim Rejections - 35 USC § 102
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.
Claim 1-7 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chicoine et al (Molecular Therapy, 2014, pages 713-724; as cited in the IDS filed 1/2/2025).
The applied Chicoine reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). The publication dated for Chicoine is 4 February 2014. The earliest effective filing date of the instant application is 17 September 2015.
Therefore rejection under 35 U.S.C. 103 CANNOT be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)© establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02. Because the reference qualifies as prior art under 102(a)(1), the provisions of MPEP 717.02 do not apply.
Regarding claim 1-6, Chicoine teaches intramuscular and isolated focal limb perfusion delivery of rAAVrh74.MCK.GALGT2 in a rhesus macaque (page 714, left col, Intramuscular delivery of rAAVrh74.MCK.GALGT2; page 714, right col, Vascular delivery of rAAVrh74.MCK.GALGT2) which induces GALGT2 overexpression accompanied by molecular changes with applications to several forms of muscular dystrophy (page 721, right col, para 1). Chicoine teaches that gene transfer using the vector rAAVrh74.MCK.GALGT2 accomplishes prevention of muscle damage in the mouse models for Duchenne muscular dystrophy (DMD), Merosin-Deficient Congenital Muscular Dystrophy Type 1A (MDC1A) and Limb-Girdle Muscular Dystrophy Type 2D/R3, (LGMD2D) (page 713, right col, para 1), hence demonstrating applicability in treating neuromuscular disorders such as DMD, MDC1A, and LGMD2D. Chicoine teaches that the tibialis anterior (TA) muscle was injected intramuscularly with 5 × 1012 of vector genome (vg) rAAVrh74. MCK.GALGT2 and for the isolated focal limb perfusion, 2 × 1012 vg/kg of rAAVrh74. MCK.GALGT2 was injected into the limb (page 714, left col, Intramuscular delivery of rAAVrh74.MCK.GALGT2; page 714, right col, Vascular delivery of rAAVrh74.MCK.GALGT2). While the Chicoine does not recite a concentration range which falls in the recited claim for the concentration of rAAV for inter-arterial limb perfusion, applicant is reminded that differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") See MPEP 2144.05 II. A.
While Chicoine teaches that the method is used on a rhesus macaque and not a human subject as recited in claim 1, Chicoine teaches that the study chose rhesus macaque since they possess neutralizing antibodies to rAAVrh74 vector and a vascular limb anatomy that is similar to humans (page 714, left col, para 1). Furthermore, Chicoine teaches the vector dose used to treat the gastrocnemius through the isolated limb perfusion method is large, mirroring the high dose used in previous human clinical trial (page 719, right col, para 1). Therefore, Chicoine teaches that the method is translatable to treating human subjects.
Regarding claim 7, whereby there is an improvement in the human subject in a group of species of metrics, it is noted that the claim is directed to an inherent result based on the methodology of the administration of the rAAVrh74.MCK.GALGT2. Because Chicoine disclose the methodology as claimed (administration of the rAAVrh74.MCK.GALGT2 intramuscularly and inter-arterial limb perfusion) the effect of the methodology is rendered obvious by the reference, absent evidence to the contrary.
Claim Rejections - 35 USC § 103
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.
Claim 1 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Chicoine et al (Molecular Therapy, 2014, pages 713-724; as cited in IDS) and further in view of NCBI gene Homo sapiens beta-4-N-acetylgalactosaminyltransferase mRNA, complete cds (GenBank: AF510036.1; first published 05-DEC-2003)
Regarding claim 1, Chicoine teaches intramuscular and isolated focal limb perfusion delivery of rAAVrh74.MCK.GALGT2 in a rhesus macaque (page 714, left col, Intramuscular delivery of rAAVrh74.MCK.GALGT2; page 714, right col, Vascular delivery of rAAVrh74.MCK.GALGT2) which induces GALGT2 overexpression accompanied by molecular changes with applications to several forms of muscular dystrophy (page 721, right col, para 1).
Regarding claim 8, Chicoine does not teach the rAAV.rh74.MCK.GALGT2 comprising the GALGT2 gene cassette set out in SEQ ID NO: 2.
NCBI teaches a gene sequence which encodes the gene GALGT2. The instant application SEQ ID NO: 2 shares 100% identity to NCBI GALGT2 gene sequence. See alignment below:
Query = SEQ ID NO: 2 of instant claims; Sbjct = NCBI GALGT2 sequence
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822
590
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633
594
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Since the sequence of GALGT2 from NCBI was known, it would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to incorporate the gene sequence taught by NCBI into the rAAVrh74.MCK.GALGT2 as taught by Chicoine to generate a rAAVrh74.MCK.GALGT2 vector for treating neuromuscular disorders. One would be motivated to do so as it was known that rAAVrh74.MCK.GALGT2 could be used to treat a neuromuscular disorder as it comprises the GALGT2 sequence in the vector and one would have a reasonable expectation of success.
Conclusion
No claims are allowed.
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/JULIANA IRENE CANDELARIA/ Examiner, Art Unit 1634
/MARIA MARVICH/ Primary Examiner, Art Unit 1634
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