DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-19 are pending.
The instant application is a divisional filing of U.S. application 16/460,397 filed 7/2/2019 now U.S. Patent 11,414,678 which is a divisional of U.S. application 14/770,991 filed 8/27/2015 now U.S. Patent 10,385,112 which is 371 filing of PCT/US2014/024119 filed 3/12/14 which claims priority to provisional application 61/782,450 filed 3/14/13.
Information Disclosure Statement
An information disclosure statement filed 7/1/2022 has been identified and the documents considered. The corresponding signed and initialed PTO Form 1449 has been mailed with this action.
Claim Objections
Claim 1 appears to have a typographical error in reciting “a vector recombinant adeno-associated viral (rAAV) vector” by using vector twice. It is appropriate just to refer to recombinant adeno-associated viral (rAAV) vector--. Appropriate correction is required.
Claim 3 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 1. Claim 4 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 13. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim 3 recites that the vector of claim 1 is a viral vector. However, by being an AAV it is a viral vector. Claim 4 recites similarly that the vector of claim 13 is a rAAV which the cell already recites.
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 10 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.
Claim 10 recites the limitation "the vector" in claim 8. There is insufficient antecedent basis for this limitation in the claim. There is no recitation of a vector in claim 8.
Claim Rejections - 35 USC § 112, first paragraph
The following is a quotation of the first paragraph of 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 1-19 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for directly administering to the eye of a subject with age related macular degeneration or diabetic retinopathy an AAV vector comprising and AAV2 capsid and comprising one of the nucleotide sequence of SEQ ID NO:2-8 wherein the nucleotide sequence is operably linked to a promoter wherein the administration leads to treatment of the subject, wherein when the capsid is selected from an AAV the AAV is selected from one of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11 and AAV12 and (re: claim 8) the specification while being enabling for inhibiting VEGF in a cell in vitro, does not reasonably provide enablement for any other embodiment. 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 or use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
1) Nature of invention. The instant claims (claim 1 and 14) are drawn to methods of treating ocular disease causing neovascularization in a subject. The method as recited requires administering a recombinant AAV vector to a retinal cell of the subject wherein the vector encodes an optimized, modified sFlt1 coding sequence. Hence, the method is directed to gene therapy. The coding sequence is one of SEQ ID NO:2-8 wherein this sequence encodes the optimized, modified sFlt1 in which the modification is a reduction in cis motifs and an increase in GC content as compared to wild type sFlt1.
Claim 8 generally refers to inhibiting VEGF in any cell in any location.
2) Scope of the invention. The claims are generically broad wherein the subject is not one that is indicated as benefitting from treatment. Rather, it is any subject. The coding sequences require expression but do not have the means to do so and finally, the method is directed at simply administration which is a broad genus of modes of administration. Finally, claims that refer to capsids from a number of AAV recite that it can be from combinations of AAV. However, these do not exist. It appears applicants intend that the capsids be from combinations of sequences from different AAV serotypes. However, the claim language is not so constructed. Hence, claims reading on significant numbers of inoperative embodiments would render claims non- enabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative. Atlas Powder Co. v. E.I. duPont de Nemours & Co., 750 F.2d 1569, 1577, 224 USPQ 409, 414 (Fed. Cir. 1984); In re Cook, 439 F.2d 730, 735, 169 USPQ 298,302 (CCPA 1971). (see MPEP 2164.08(b).
Claim 8 is extremely broad in that the location and the cell type as well as the mode of delivery is not specified.
3) Number of working examples and guidance. The specification teaches that ocular disorders associated with neovascularization include, for example, retinal damage, exudative age-related macular degeneration, diabetic retinopathy, corneal neovascularization, choroidal neovascularization, neovascular glaucoma, cyclitis, Hippel-Lindau Disease, retinopathy of prematurity, pterygium, histoplasmosis, iris neovascularization, macular edema and glaucoma-associated neovascularization. Methods of treatment at the time of filing involved laser therapy which had limited success in such disorders. The instant application sought to establish a more effective means to treat ocular disease with neovascularization. The proposed method involved administration of sequence encoding sFlt1 which has been optimized and modified. The modifications include reduced cis motifs and increased GC content. The AAV2 vectors introduced into mice had a reduced leakage and improved choroidal neovascularization.
4) State of the art. sFlt1 is known in the art, Verrax et al (ACS publication, 2011, pages 701-708, see abstract) and Lai et 1 (Immunol and Microbiol, 2009, pages 4279-4287; see purpose) wherein Lai teaches it can be used to treat retinal cells (see methods). However, the art does not teach increased GC content and reduced cis motifs which improved the reduction in neovascularization as set forth in the disclosure. The art teaches that the method is relevant for age related macular degeneration or diabetic retinopathy (see Lai et al ibid, discussion and Heier et al (Lancet, 2017, abstract and page 53)
5) Unpredictability of the art. The claims simply require that the method be directed at a subject in need thereof. This subject is one that require prevention or reduction of reducing ocular neovascularization. Hence, applicants do not identify the subject wherein the subjects also include those for whom the disease must be prevented. This requires predicting the subjects that would require treatment which would be highly unpredictable. In humans, the claimed diseases are usually established before therapy is offered. The specification does not adequately teach how to effectively predict for whom prevention would be required. One establishes a large genus of target subjects for whom the method is intended, however, establishing whether a person or persons actually requires the treatment is a highly unpredictable art. Screening procedures for indications of those requiring inhibition of the onset of disease are unknown and highly prejudicial leading to conditions in which those who require the treatment cannot be distinguished from those who do not. The physiological art is recognized as unpredictable. (MPEP 2164.03.) In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In this case, applicants exacerbate the unpredictability of the art by reciting subjects to be targeted for whom the disease must be prevented.
Secondly, the modifications that are shown for increased GC content and reduced cis motifs are found in SEQ ID NO:2-8. These sequences provide the required function. 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, 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.
Claim 14 is drawn to methods of preventing or reducing choroidal neovascularization in a subject using any vector. While the disclosure teaches introduction of sFlt1 into mice to reduce leakage and improved choroidal neovascularization, at the time of filing, the virus that was found to be successful for eye delivery was AAV2 (Han et al, Molecular Therapy, 2023, see Discussion) and in the disclosure the method is performed only with AAV2. At issue with the results is that the art has demonstrated difficulties in performing such methods generically and especially as gene delivery has been a persistent problem for gene therapy protocols wherein the route of delivery itself presents an obstacle to be overcome for the application of the vector therapeutically. The challenge is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Mingozzi and High review the issues associated with gene delivery with AAV known at the time of filing. Specifically, there lacks an adequate means of overcoming obstacles such as organ barriers, failure to persist, side-effects in other organs, T-cell responses, virus neutralizing antibodies, humoral immunity and normal tropism of the vector to other organs limits the successful means by which the nucleic acid can be administered. A high concentration of vector locally is required. Given the means and ease with which the eye is targeted, the claims should for enablement be limited to these methods which are demonstrated to work (see Liu et al). Furthermore, this method is relevant for AMD (see Yeo et al, Frontiers in Pharm, 2019, pages 1-19 especially abstract).
As to claim 8, the claim refers to inhibiting VEGF in a cell simply by administering the sequence encoding sFLT1 described above. The cell should be a VEGF comprising cell and the method one that would deliver for expression in that cell. The disclosure provides for delivery to a mammalian cell in vitro to satisfy the broadly claimed method of claim 8. The disclosure teaches that the method, however, is designed to inhibit VEGF specifically for retinopathy due to diabetes and for AMD.
[0006] It has been found that vascular endothelial growth factor (VEGF) is a major stimulatory factor for retinal neovascularisation. It is unlikely to be the only stimulatory factor but it is nevertheless the key factor involved. VEGF is upregulated by hypoxia and its levels are increased in the retina and vitreous of patients or laboratory animals with ischaemic retinopathies. Also, increased expression of VEGF in retinal photoreceptors stimulates neovascularisation in the retina and VEGF antagonists inhibit retinal or iris neovascularisation in animal models.
6) Undue experimentation. The claims have been evaluated in light of the specification and the prior art available at the time of filing. "However, claims reading on significant numbers of inoperative embodiments would render claims non- enabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative. Atlas Powder Co. v. E.I. duPont de Nemours & Co., 750 F.2d 1569, 1577, 224 USPQ 409, 414 (Fed. Cir. 1984); In re Cook, 439 F.2d 730, 735, 169 USPQ 298,302 (CCPA 1971). (see MPEP 2164.08(b). What is necessary is an indication of a preferred and functional means of overcoming the obstacles associated with the art detailed below.
Conclusion
The parent applications are true divisional of the instant application. Claims 1-19 are drawn to methods of delivery of optimized, modified coding sequences for soluble fms-like tyrosine kinase-1. Claim 8 requires inhibition of VEGF wherein the only disclosed use as set froth above is to treat neovascularization and hence reads on the subject matter.
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/MARIA MARVICH/
Primary Examiner, Art Unit 1633
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