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 .
Claims 12-14 have been canceled. Claims 1-11, 15, 16 are pending.
Claim Objections
The structures of the AAV in claim 1 can be written out more simply. The phrase pharmaceutical composition does nothing more to the function of the AAV as compared to an AAV in saline or water. The metes and bounds of diseases associated with a ARSA mutation cannot be determined. The term “recombinant” is redundant because the AAV encodes an exogenous protein. The claim is missing the fact that it is an AAV vector. Or perhaps applicants are attempting to claim an AAV particle. Either way, it needs to be made clear. It is assumed the metes and bounds of an AAVhu68 capsid was well-known (WO 2018/160582). The metes and bounds of a CB7 and CB promoter cannot be determined. Perhaps it relates to a chicken beta actin promoter. Perhaps the metes and bounds of the structures/functions associated with a CB7 promoter were well-known, but extensive explanation will be required. The linkage of the hARSA coding sequence to the CB7 can be simplified. The term “repeats” in line 5 should singular. The phrase “which directs the hARSA expression” is redundant because the promoter and coding sequence are operably linked. The function of SEQ ID NO: 1 (or anything at least 95% identical to it) in line 10-11 cannot be determined, but it appears to relate to the hARSA coding sequence in line 7; the structure and function of the hARSA coding sequence should be put together. Any AAV can be delivered intrathecally in water, saline, or any other carrier, so it is unclear how the last 4 lines further limits the structures/functions of the AAV.
Assuming claim 1 is drawn to an AAV particle, the claim can be written more simply as ---A composition comprising:
a) an adeno-associated viral (AAV) particle comprising an AAVhu68 capsid and a genome comprising:
i) a 5' AAV inverted terminal repeat (ITR),
ii) a promoter operably linked to a nucleic acid sequence encoding human Arylsulfatase A (hARSA) that is 95-99.9% identical to nucleotides 1-1521 of SEQ ID NO: 1,
iii) a polyA signal, and
iv) a 3' AAV ITR; and
b) an aqueous buffer, carrier, excipient, or preservative.
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.
Written Description
Claims 1-11, 15, 16 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 specification lacks written description for any AAV encoding hARSA for treating metachromatic leukodystrophy or any disease associated with an arylfulfatse A (ARSA) gene mutation as required in claims 1 and 15.
Claim 1 is drawn to a pharmaceutical composition for use in treating metachromatic leukodystrophy or a disease associated with an arylsulfatase A (ARSA) gene mutation, said pharmaceutical composition comprising recombinant adeno-associated virus (rAAV) comprising an AAVhu68 capsid; and a vector genome comprising: a 5' AAV inverted terminal repeats (ITR), a CB7 promoter comprising a CMV IE enhancer and a CB promoter, and a nucleic acid sequence encoding a functional human Arylsulfatase A (hARSA) operably linked to regulatory sequences comprising the CB7 promoter which direct the hARSA expression, a polyA signal, and a 3' AAV ITR wherein the hARSA coding sequence comprises a sequence of nucleotide (nt) 1 to nt 1521 of SEQ ID NO: 1, or a sequence at least 95% to 99.9% identical thereto which encodes a functional hARSA; andat least one aqueous buffer, at least one carrier, at least one excipient and/or a least one preservative, said pharmaceutical composition being deliverable in a single therapeutic dose via intrathecal administration.
It is assumed the metes and bounds of AAVhu68 were well-known (WO 2018/160582).
It is unclear whether applicants are attempting to claim a composition comprising an AAV vector or an AAV particle. Either way, it needs to be made clear. It is assumed the metes and bounds of an AAVhu68 capsid was well-known.
The metes and bounds of a CB7 and CB promoter cannot be determined. Pg 97 says it’s a “regulatory element derived from the chicken β-actin promoter” and “human cytomegalovirus immediate-early enhancer (CMV-IE)”; however, the metes and bounds of the regulatory element “from the CBA promoter” cannot be determined. Nor can it be determined what/how/which part of the “regulatory element” was “derived”.
Any AAV can be delivered intrathecally in water, saline, or any other carrier, so it is unclear how the last 4 lines further limits the structures/functions of the AAV.
Example 1 (pg 97) describes making an AAVhu68 vector encoding hARSA operably linked to a “regulatory element derived from the chicken β-actin promoter” and “human cytomegalovirus immediate-early enhancer (CMV-IE)” along with two ITRs and a polyA signal.
Example 2 (pg 111) describes administering the vector to wild-type mice via intracerebroventricular (ICV) administration for a “pharmacology and dose range study”.
Example 3 (pg 113) describes administering the vector to wild-type mice via intracerebroventricular (ICV) administration for a “Cell tropism study in mice”.
Example 4 (pg 115) describes administering the vector to wild-type macaques via the “intra-cisterna magna” for “Transgene Product Expression and Cellular Localization”.
Example 5 (pg 120) describes administering the vector to wild-type macaques via the “intra-cisterna magna” for “dose ranging pharmacodynamic and pilot safety study”.
Example 6 (pg 126) describes a mouse whose genome is homozygous for an inactivated ARSA gene.
Example 7 (pg 145) describes administering the vector to ARSA knockout mice via ICV administration for ARSA expression and efficacy. Summary of results are on pg 152-153.
Example 8 (pg 153) optimizes the dose for ICV.
Example 9 (pg 167) appears to be an optimization study just like example 8.
Example 10 (pg 183) is a toxicology study in macaques.
Example 11 (pg 208) is a sensory neuron toxicity in non-clinical AAV studies.
Example 12 (pg 208) is a prophetic trial in humans with an inactivated ARSA gene and is limited to ICV administration.
The specification fails to correlate treating mammals to treating invertebrates, insects, fish, amphibians, reptiles or birds with a mutant ARSA gene as broadly encompassed by claims 1 and 15.
Example 7 is limited to modifying symptoms of an inactivated ARSA gene in mice by injecting the vector via ICV. The specification fails to correlate administering the vector via ICV to any route of administration as broadly encompassed by claims 1 and 15, specifically intracisternal administration as required in claim 9 and 15.
Accordingly, the claims lack written description for non-mammalian embodiments and ICM or other routes of administration other than ICV.
Enablement
Claims 1-11, 15, 16 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 an AAV vector encoding ARSA operably linked to a promoter and administering the vector via ICV to a mammal that has an inactivated ARSA gene such that symptoms of ARSA inactivation are ameliorated, does not reasonably provide enablement for the claims as broadly written. 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/use the invention commensurate in scope with these claims.
The specification does not enable making/using any AAV encoding hARSA for treating metachromatic leukodystrophy or any disease associated with an arylfulfatse A (ARSA) gene mutation as required in claims 1 and 15.
Claim 1 and its scope are recited above.
The examples are recited above.
The specification fails to correlate treating mammals to treating invertebrates, insects, fish, amphibians, reptiles or birds with a mutant ARSA gene as broadly encompassed by claims 1 and 15.
Example 7 is limited to modifying symptoms of an inactivated ARSA gene in mice by injecting the vector via ICV. The specification fails to correlate administering the vector via ICV to any route of administration as broadly encompassed by claims 1 and 15, specifically intracisternal administration as required in claim 9 and 15.
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to use non-mammalian embodiments or to use ICM or other routes of administration other than ICV.
Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-11, 15, 16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The metes and bounds of a CB7 and CB promoter in claim 1 and 15 cannot be determined. Perhaps it relates to a chicken beta actin promoter. But the metes and bounds of the structures/functions associated with a CB7 promoter are not taught in the specification and cannot be found in the art at the time of filing.
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.
Claims 1-11, 15, 16 are rejected under 35 U.S.C. 102a1 as being anticipated by Hordeaux (WO 2020/227166).
Hordeaux discloses a pharmaceutical composition comprising an AAV particle for treating MLD comprising an AAVhu68 capsid, wherein the genome of the AAV comprises: 5’ and 3’ ITRs, a hARSA sequence identical to SEQ ID NO: 1 (SEQ ID NO: 1) operably linked to a CB7 promoter, and a polyA signal. This is equivalent to claim 1.
The genome of the AAV has a kozak sequence or intron as required in claim 2.
Hordeaux taught a hARSA sequence identical to SEQ ID NO: 1 (SEQ ID NO: 1) as required in claim 3.
The 5’ and 3’ ITRS and components of Hordeaux add up to the cassette of SEQ ID NO: 28 as required in claim 4.
Hordeaux taught the ITRs were from Carter (1990) (para 183-184) which are SEQ ID NO: 26 and 25 as required in claim 5.
Hordeaux taught components that add up to SEQ ID NO: 27 as required in claim 6.
Hordeaux taught AAVhu68 was encoded by SEQ ID NO: 7 (claim 10) as required in claim 7.
Hordeaux taught the formulation in claim 8 (claim 12).
Hordeaux taught the route of administration, e.g. via intra-cistema magna, in claim 9 (claim 15, 23, 29).
Hordeaux taught the dosages in claims 10 and 11 (claims 27).
All of the limitations in claims 15 and 16 are taught by Hordeaux and are discussed above.
Conclusion
No claim is allowed.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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