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 Objections
Claim 25 is objected to because of the following informalities: the claim does not end with a period. Appropriate correction is required.
Claim 18 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claim has not been further treated on the merits.
Claim 22 is objected to because of the following informalities: the claim recites a promoter “…comprising a SEQ ID NO: 1..”, which is grammatically clumsy and potentially confusing. Appropriate correction is required (e.g. “…comprising SEQ ID NO: 1…”). This objection affects all dependent claims.
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 1, 3-17, 19-21 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 encompass promoters, vectors and nucleic acids comprising a nucleic acid sequence with 95% identity to SEQ ID NO: 1, e.g. as recited in claim 1. According to the definitions in the specification, the variance between SEQ ID NO: 1 and the claimed 95% identity can be at any position in SEQ ID NO: 1 and can be a change to any nucleotide.
However, applicant was not in possession of the claimed genera of promoters, vectors and nucleic acids (all having a generic promoter function) as elements of the claimed products and methods in the absence of providing sufficient structural and functional characteristics of the genera of each of these elements broadly encompassed by the instant claim language, coupled with a known or disclosed correlation between function and structure.
However, the instant application has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genera of nucleic acid sequences with promoter function encompassing structurally related or structurally unrelated, functionally related or functionally unrelated sequences.
"It is not sufficient to define the recombinant molecule by its principal biological activity, e.g. having protein A activity, because an alleged conception having no more specificity than that is simply a wish to know the identity of any material with that biological property." Colbert v. Lofdahl, 21 USPQ2d, 1068, 1071 (BPAI 1992). Mere idea or function is insufficient for written description; isolation and characterization at a minimum are required
The claims do not recite sufficient written description of the structural and functional characteristics coupled with a known or disclosed correlation between function and structure, since the disclosure fails to describe the common attributes or characteristics that identify each member of the genera of nucleic acid sequences with promoter function as broadly encompassed by the claimed invention. Therefore, there is insufficient written description of the claimed genera of nucleic acid sequences with promoter function in the absence of defining the relevant identifying characteristics such as the structure or other physical and/or chemical characteristics of the claimed genera.
The written description requirement for a genus may be satisfied by sufficient description of a representative number of species by actual reduction to practice or by disclosure of relevant identifying characteristics, i.e. structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between structure and function, or by a combination of such identifying characteristics, sufficient to show that applicant was in possession of the claimed invention. The court and the Board have repeatedly held (Amgen Inc. v. Chugai Pharmaceutical Co. Ltd.,18 USPQ2d 1016 (CA FC, 1991); Fiers v. Revel, 25 USPQ2d 1601 (CA FC 1993); Fiddes v. Baird, 30 USPQ2d 1481 (BPAI 1993) and Regents of the Univ. Calif. v. Eli Lilly & Co., 43 USPQ2d 1398 (CA FC, 1997)) that an adequate written description of a nucleic acid requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it, irrespective of the complexity or simplicity of the method; what is required is a description of the nucleic acid itself. It is not sufficient to define DNA solely by its principal biological property, because disclosure of no more than that, as in the instant case, is simply a wish to know the identity of any DNA with that biological property. Naming a type of material generically known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material. When one is unable to envision the detailed constitution of a complex chemical compound having a particular function, such as a nucleic acid or protein, so as to distinguish it from other materials, as well as a method for obtaining it, conception has not been achieved until reduction to practice has occurred, i.e., until after the nucleic acid has been isolated. Thus, claiming all DNA’s that achieve a result without defining what means will do so is not in compliance with the description requirement. Rather, it is an attempt to preempt the future before it has arrived.
Applicant is relying upon certain biological activities and the disclosure of a single species (e.g., SEQ ID NO: 1) to support entire genera. In the instant case, applicants only disclose SEQ ID NO: 1. Neither applicants nor the prior art disclose other promoters that vary from SEQ ID NO: 1. Applicants are claiming variants of SEQ ID NO: 1 by function only, without a correlation between structure and function. Applicants provide no disclosure of what specific nucleotide residues of the instantly disclosed SEQ ID NO: 1 are responsible for the observed promoter activity.
To put the situation in perspective, the number of possible residue changes or substitutions in a sequence 95% identical to a sequence 603 nucleotides in length (SEQ ID NO: 1 is 603) is 30. The number of possible nucleotide or amino acid sequences that are of a given % identity relative to a reference sequence, where all differences between the possible sequences and the reference sequence are substitutions, can be calculated by the following formula:
Xn . L!/ n! (L-(n-1)! -where X is the number of different residues that can be substituted for a residue in the reference sequence, L is the length of the reference sequence, n is the maximum number of residues that can be substituted relative to the reference sequence at a given % identity. For a nucleotide sequence, X is 3 (alternate nucleotides); for an amino acid sequence, X is 19 (alternate amino acids).
For a 603 residue nucleotide sequence that is at least 95% identical to a reference sequence of 603 nucleotides, e.g. SEQ ID NO: 1, the number of possible sequences having 30 substitutions relative to the reference is approximately 9 x 1061. While limiting the scope of potential sequences to those that are at least 95% identical to a reference, for example, greatly reduces the number of potential sequences, it does not do so in any meaningful way.
Claims 19-21 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc. 8 USPQD2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is a conclusion reached by weighing several factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQQ2d 1400 (Fed. Cir. 1988) and include the following:
State of the prior art and level of predictability in the art: In spite of considerable interest in gene therapy using rAAV the art of record contains no description of methods of treating a disease with an rAAV comprising a vector or genome that comprises only a promoter. For example, WO 2006/101457 (of record) teaches construction of viral vectors comprising an AAV genome designed to comprise and express therapeutic transgenes in the treatment of neurodegenerative disorders. Likewise, WO 2020/112802 (of record) teaches rAAV vectors comprising genomes designed to comprise and express therapeutic inhibitory nucleic acids or transgenes in the treatment of, e.g. Alzheimer’s disease. The art cited is silent with regard to treatment of any disease with rAAV vectors with genomes that comprise only AAV background sequences (e.g. ITR’s) and a promoter. Thus, the structural features that provide the basis for treatment of a disease in such rAAV vectors comprising only a heterologous promoter are not well understood. This clearly evidences that such rAAVs were at an early stage of development at the time of filing and that the skilled artisan would not know how to make and use these promoter-only vectors in methods of treatment without explicit guidance from the specification or significant empirical experimentation.
Amount of direction provided by the inventor and existence of working examples:
In the working examples, the specification teaches in vivo astrocyte-specific expression of GFP from the claimed promoter using rAAV vectors to deliver the GFP transgene. The specification also discloses well-known methods for manipulation of such vectors and other transgenes that may be expressed from the vectors. It is noted no therapeutic effect is provided by GFP (a marker gene) in any neurodegenerative disease, and no disease models or organisms were tested for any in vivo therapeutic value of the claimed rAAV, even those that might include a therapeutic transgene.
Although the specification suggests a method by which one might construct a rAAV having the features identified as necessary, there is no evidence that the method contemplated would actually produce a therapeutic result in neurodegenerative disease patient or subject. Thus, in order to make and use the invention as claimed, the skilled artisan would have to further develop rAAVs such that they were capable of functioning in the wide variety of treatment methods and diseases recited in the claims.
Nature of the invention and Breadth of the claims: The claims are directed to methods of rAAV gene therapy of neurodegenerative diseases, the properties of which have been outlined above. The claims are not limited to any particular neurodegenerative disease, delivery method, and do not even require a therapeutic transgene. Thus, the claimed treatment methods encompass a divergent genus of potential methods dependent upon the patient and disease to be treated. As the claims encompass a wide variety of methods, it is incumbent upon the disclosure to set forth the manner and process of making and using the claimed rAAVs in a variety of neurodegenerative diseases that is commensurate with the scope of protection sought.
Relative skill of those in the art and quantity of experimentation needed to make or use the invention: Although the level of skill in the art of manipulating rAAV vectors is high, the level of skill in the art of using rAAVs that comprise only a heterologous promoter to treat disease is low. One would not be able to treat a given neurodegenerative disease with such vectors given no more than the teachings available at the time of filing without undue experimentation. The art of record does not provide a single working example of treating a neurodegenerative disease with rAAV vectors as instantly claimed. Likewise, all of the teachings in the instant application are directed to expressing GFP in vivo and essentially no direction as to how to make and use the claimed rAAV in methods of treatment. Given the broad scope of the claims, the early developmental stage and the unpredictability of the art at the time of filing, making embodiments of the claimed invention would clearly require undue experimentation. Therefore, the claims are properly rejected under 35 USC 112, first paragraph, as lacking enablement.
Given the above analysis of the factors which the courts have determined are critical in determining whether a claimed invention is enabled, it must be considered that undue and excessive experimentation would have to be conducted by the skilled artisan in order to practice the claimed invention.
Allowable Subject Matter
Claim 2 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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/MICHAEL D BURKHART/Primary Examiner, Art Unit 1638