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 .
Priority
The instant application was filed 01/23/2025 and is a Divisional of 18209041 , filed 06/13/2023 which is a continuation of 16955715 , filed 06/18/2020, which is a National Stage entry of PCT/US18/66512 with an international filing date: 12/19/2018 and claims priority from provisional application 62607665 , filed 12/19/2017.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/12/2025, 8/19/2025, 9/19/2025 is being considered by the examiner.
Claim Objections
Claim 113-131 are objected to because of the following informalities:
Claim 113 is objected to as it recites “VEGF” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Claim 116 is objected to as it recites “CAG,” “CBA,” and “CMV” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Claim 121 is objected to as it recites “IL2” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Appropriate correction is required.
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 113-118. 120-131 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.
Independent claim 113 is drawn to, “first coding sequence that encodes a first polypeptide, wherein the first polypeptide comprises an antibody heavy chain variable domain operably linked to a first signal peptide, and(ii) a second coding sequence that encodes a second polypeptide, wherein the second polypeptide comprises an antibody light chain variable domain operably linked to a second signal peptide, wherein the first coding sequence comprises a sequence having at least 96% identity to SEQ ID NO: 40, and the second coding sequence comprises a sequence having at least 96% identity to SEQ ID NO: 44, or both, and wherein the first and second polypeptides specifically bind to one or more mammalian VEGF proteins.” Thus the claims encompass any coding sequence comprising a sequence having 96% with SEQ ID NO 40 or SEQ ID NO 44. Thus it encompasses fragments of SEQ ID NO 40 or SEQ ID NO 44. Further the claims encompass the first and second polypeptides bind any mammalian VEGF protein.
The instant claims above are drawn to a genus of antibodies defined only by the epitopes they bind and comprising a fragment having 96% identity SEQ ID NO 40 and a fragment having 96% identity to SEQ ID NO 44. They are not defined by any structure other than being generically antibody as defined by the specification. Yet, the specification provides no additional antibodies that bind any of the epitopes recited. When one goes to the instant specification to identify a representative number of species to define the claimed genus with respect to antibodies with six CDRs that bind the recited epitopes, SEQ ID NO 5 and SEQ ID NO 6. Even if the prior art is aware of additional antibodies, the totality of known antibodies would not be representative of each entire genus for the reasons discussed below.
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genus antibody with specific epitope, Applicant must adequately describe representative antibodies to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through 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 function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. . A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the antibodies claimed can have any CDR set, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.”
One of skill in this art cannot envision the structure of any other antibodies which encompass a sequence including fragments having 96% sequence identity with SEQ ID NO 40 and 44 other than the single species provided by Applicant. Therefore, since only a single species is provided to represent these genera, the claims encompassing the same clearly fail the written description requirement.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). Since the CDR set of each antibody is responsible for antigen binding function of an antibody, and said set varies structurally from antibody to antibody, there is no correlation between structure and function between the members of an antibody genus. One cannot “represent” the entire genus defined only by function with any structural consensus. Thus, functional language should not be used to define an antibody genus. Rather, structure should be used.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. Four species is certainly not adequate.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
Since only a single species or only a few species of antibodies are taught within the claimed genera above, those that bind the recited epitopes and at specific affinities, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe these genera. Given the well-known high level of polymorphism of immunoglobulins / antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of every first and second polypeptides comprising a sequence having at least 96% identity with SEQ ID NO 40 and a polypeptide comprising a sequence having at least 96% identity with SEQ ID NO 44 and a polypeptide and specifically bind any mammalian VEGF proteins, broadly encompassed by the claimed invention. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
Owed to the variation among antibodies with respect to their CDRs, the structure of antibodies that correlates with their function, it is very difficult to provide adequate representation of a functionally defined antibody genus. There is unlikely to be any CDR structure shared by the entire genus, for example. Also, the disclosure of one set of antibody CDRs does not guide one of skill to the next set of CDRs. This is because it is well-known in this art that mutation of CDR residues leads to loss of antigen binding. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract). Thus, while applicant has described one or a few species within each of the genera recited, and the art may provide more, each genus is very large and would encompass antibody structures (CDR sets) that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the antibody structures encompassed by the claimed genera only defined by function. Any future antibody structure may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the recited genera of antibodies. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
Benner et al (Trends in Genetics (2001) volume 17, pages 414-418) teaches that, “Here, the ‘homology-implies-equivalency’ assumption is restricted to a subset of homologs that diverged in the most-recent common ancestor of the species sharing the homologs. This strategy is useful, of course. But it is likely to be far less general than is widely thought. Two species living in the same space, almost by axiom, cannot have identical strategies for survival. This, in turn, implies that two orthologous proteins might not contribute to fitness in exactly the same way in two species” (see page 414, 3rd column last full paragraph). Benner specifically describes that although the leptin gene homologs have been found in mice and humans, their affect is different (see page 414, 3rd column last paragraph-3rd column page 415). Benner specifically teaches that the leptin gene in mice plays a major role in obesity, but no such effect has been demonstrated in humans due perhaps to the different evolutionary forces. Benner thus teaches that the activity and function of genes in different species is unpredictable.
Burgin (Journal of Mammalogy, 99(1):1–14, 2018) teaches, “We found 6,495
species of currently recognized mammals.”
Holmes, (The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol 6, 209 (2005). https://doi.org/10.1186/gb-2005-6-2-209) teaches there are multiple members of VEGF family.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite all parental CDRs of the species disclosed since it is these structures together that are required to bind the recited antigen.
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 113-131 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.
Claim 113 recites, “wherein the first and second polypeptides specifically bind to one or more mammalian VEGF proteins.” The recitation of specifically binds suggest there is non-specifically binds. Thus specifically binds is a relative term. Review and searching of the specification did not reveal a standard to differentiate specifically binds from non-specifically binds. Thus the metes and bounds are unclear.
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.
Claim(s) 113-119, 122-123, 124-126 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wantanbe (Gene Therapy (2010) 17, 1042–1051; doi:10.1038/gt.2010.87).
Claim 113 recites, “wherein the second polypeptide comprises an antibody light chain variable domain operably linked to a second signal peptide, wherein the first coding sequence comprises a sequence having at least 96% identity to SEQ ID NO: 40, and the second coding sequence comprises a sequence having at least 96% identity to SEQ ID NO: 44, or both.” Thus the broadest reasonable interpretation is the claims encompass fragments of SEQ ID NO 40 and or SEQ ID NO 44.
With regards to claim 113,118-119 Wantanbe teaches, “AAVrh.10aVEGF encodes the anti-human VEGF light chain and heavy chain sequence separated by a poliovirus internal ribosome entry site to facilitate expression of both protein subunits from a single promoter.21,27 The expression cassette in the AAVrh.10aVEGF vector contains (50 to 30) the cytomegalovirus promoter, the anti-human VEGF light chain coding sequence, the poliovirus internal ribosome entry site, the anti-human VEGF heavy chain-coding sequence and the simian virus 40 polyadenylation signal. Synthetic antibody heavy and light chain variable domains selected for the study were derived from the protein sequence for antibody A.4.6.1, the murine antibody that was humanized to generate bevacizumab.29 The coding sequences for the human VEGF-A binding site are identical to that of bevacizumab.” (page 1048, 1st column AAV vector).
With regards to claim 115-116, Wantanbe teaches, “AAVrh.10aVEGF vector contains (50 to 30) the cytomegalovirus promoter.” (page 1048, 1st column AAV vector).
With regards to claim 117, Wantanbe teaches, “AAVrh.10aVEGF vector contains (50 to 30) the cytomegalovirus promoter.” (page 1048, 1st column AAV vector).
With regards to claims 122-123, Wantanbe teaches, “All AAV vectors were based on the non-human primate derived AAV serotype rh.10 capsid with the AAV serotype 2 50 and 30 inverted terminal repeats and the transgene under the control of the cytomegalovirus promoter.”) [age 1048. 1st column (AAV vectors).
With regards to claim 124-126, Wantanbe teaches the use of PBS for administration of the AAVrh.10aVEGF vector. (page 1048, 2nd column Anti-VEGF-A antibody levels after local administration of AAVrh.10aVEGF).
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.
Claim(s) 113-119, 122-131 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gao (Proceedings National Academy of Sciences USA ((vol 112) pages 14676-14681), Wantanbe (Gene Therapy (2010) 17, 1042–1051; doi:10.1038/gt.2010.87), Shu (HUMAN GENE THERAPY, VOLUME 27 NUMBER 9, pages 687-699).
Claim 113 recites, “wherein the second polypeptide comprises an antibody light chain variable domain operably linked to a second signal peptide,wherein the first coding sequence comprises a sequence having at least 96% identity to SEQ ID NO: 40, and the second coding sequence comprises a sequence having at least 96% identity to SEQ ID NO: 44, or both.” Thus the broadest reasonable interpretation is the claims encompass fragments of SEQ ID NO 40 and or SEQ ID NO 44.
Gao teaches, “In our study, first, we used the sciatic nerve model to characterize the effect and mechanisms of anti-VEGF treatment on neurological function. We revealed that anti-VEGF treatment alleviates tumor edema, which may further result in decreasing muscle atrophy and increasing nerve regeneration and, thus, improves neurological function. Second, we used the intracranial window model to monitor in real time the effect of anti-VEGF treatment on tumor vasculature. We showed that anti-VEGF treatment transiently normalizes the tumor vasculature, leading to improved perfusion and oxygen delivery. Using intravital microscopy imaging technique, we further defined the timing of this transient effect, termed the “normalization window,” in schwannoma models. Because oxygen is a potent radiosensitizer, finally, we showed that radiation therapy applied during the normalization window is most effective, and combined anti-VEGF and radiation therapy is superior to each monotherapy. Anti-VEGF and radiation combination therapy may thus help reduce the dose of each therapy and minimize treatment-associated adverse effect in NF2 patients.” (14676, 2nd column)
Gao does not specifically teach the use of AAV- anti-VEGF treatment for treatment of inner.
However, Wantanbe teaches, “AAVrh.10aVEGF encodes the anti-human VEGF light chain and heavy chain sequence separated by a poliovirus internal ribosome entry site to facilitate expression of both protein subunits from a single promoter.21,27 The expression cassette in the AAVrh.10aVEGF vector contains (50 to 30) the cytomegalovirus promoter, the anti-human VEGF light chain coding sequence, the poliovirus internal ribosome entry site, the anti-human VEGF heavy chain-coding sequence and the simian virus 40 polyadenylation signal. Synthetic antibody heavy and light chain variable domains selected for the study were derived from the protein sequence for antibody A.4.6.1, the murine antibody that was humanized to generate bevacizumab.29 The coding sequences for the human VEGF-A binding site are identical to that of bevacizumab.” (page 1048, 1st column AAV vector).
Shu teaches,” One of the most promising approaches to develop treatment for genetic hearing loss is gene therapy. Gene therapy offers the possibility to supplement normal copies of genes whose functions are lost to correct gene defects. Adeno-associated virus (AAV) has been increasingly used as a primary choice of delivery vehicle for inner ear gene therapy because of its limited immunogenicity and toxicity, and its success in gene therapy programs for diverse genetic disorders such as retinitis pigmentosa, hemophilia A and B, and San Filippo A in humans.3–12 The elaborate structure and exquisite function of the inner ear require coordinated action of diverse inner ear cell types, including the sensory hair cells, supporting cells, neurons, and stria vascularis. Gene defects in any of these cell types result in genetic hearing loss.13–15 For instance, mutations in MYO7A, a gene affecting hair cell function, cause Usher syndrome type IB; GJB2 mutations in supporting cells and fibrocytes are responsible for the most common form of recessive deafness known as DFNB1, and mutations in NDP affecting the function of the stria vascularis and auditory neurons give rise to a form of syndromic deafness known as Norris disease.16–18 Targeting those cell types would likely require AAV with different tropisms. Further, other factors, including the effect on the delivery to young versus mature inner ears, the route of delivery, the control of expression of exogenous genes, and the impact of titer and longterm expression status, have yet to be determined.” (687-688). Shu teaches, “It is increasingly recognized that AAV is an important vehicle for inner ear gene delivery, making it feasible to study gene function, and ultimately may represent a treatment for hearing loss. Previous studies have evaluated AAV vectors, including AAV1, 2/1, 2, 5, 6, and 8, in the inner ear.9,24–26 The present study evaluated additional AAV serotypes for their infectability in young and adult mouse inner ears. The study identified AAV viral vectors that can be used for targeted delivery into specific inner ear cell subtypes in neonatal and adult animals, with long-term expression patterns.” (page 696-697). Shu teaches, “The total delivery volume for each injection was *0.2µl per cochlea and the release was controlled by a micromanipulator at the speed of 3nl/sec.”
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to treat inner ear with AAVrh.10aVEGF for treatment of NF2. The artisan would be motivated to get persistent expression of bevacizumab in the inner ear in subjects by cochlear injection with NF view of the teachings of Gao. The artisan would have a reasonable expectation of success as Shu teaches AAV for treatment of inner ear. (claims 127-131)
With regards to claims 122-123, Wantanbe teaches, “All AAV vectors were based on the non-human primate derived AAV serotype rh.10 capsid with the AAV serotype 2 50 and 30 inverted terminal repeats and the transgene under the control of the cytomegalovirus promoter.” )[age 1048. 1st column (AAV vectyors).
With regards to claim 115-116, Wantanbe teaches, “AAVrh.10aVEGF vector contains (50 to 30) the cytomegalovirus promoter.” (page 1048, 1st column AAV vector).
With regards to claim 117, Wantanbe teaches, “AAVrh.10aVEGF vector contains (50 to 30) the cytomegalovirus promoter.” (page 1048, 1st column AAV vector).
With regards to claim 124-126, Wantanbe teaches the use of PBS for administration of the AAVrh.10aVEGF vector. (page 1048, 2nd column Anti-VEGF-A antibody levels after local administration of AAVrh.10aVEGF).
Claim(s) 120 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gao (Proceedings National Academy of Sciences USA ((vol 112) pages 14676-14681), Wantanbe (Gene Therapy (2010) 17, 1042–1051; doi:10.1038/gt.2010.87), Shu (HUMAN GENE THERAPY, VOLUME 27 NUMBER 9, pages 687-699as applied to claims 113-119, 122-131 above, and further in view of Szymczak (Nature Biotechnology (2004, volume 22, pages 589-594.
The teachings of Gao, Wantanbe and Shu are set forth above.
While the teachings of Gao, Wantanbe and Shu suggest AAV constructs encoding bevacizumab. They do not specifically teach the use of an thosea asigna virus 2A peptide.
However, Szymczak teaches, “Several viruses use 2A peptides, or 2A-like sequences, to mediate protein cleavage2,4. These include members of the Picornaviridae virus family, such as foot-and-mouth disease virus (FMDV) and equine rhinitis A virus (ERAV), and other viruses such as the porcine teschovirus-1 and the insect virus Thosea asigna virus (TaV)3. The 2A peptide consensus motif (2A, Asp-Val/Ile-Glu-X-Asn-Pro-Gly; 2B, Pro) is extremely rare and is always associated with cleavage activity between the 2A glycine and the 2B proline (Fig. 1a).” Szymczak teaches, “Several difficulties have been reported in the use of IRES elements and additional promoters in multicistronic vectors. The larger size of IRES elements and additional promoters, compared with 2A sequences, can be a substantial limitation for vectors with limited cloning capacity, such as rAAV and retroviral vectors14 and may also lead to reduced viral titers15. Additionally, internal promoters can be downregulated in retroviral vectors through promoter interference16. Furthermore, the use of multiple IRES elements can lead to competition for translation factors and/or homologous recombination17 and can vary profoundly in different cell types18. Lastly, IRES-dependent expression can be significantly lower than cap-dependent expression19. All of these problems are reduced or eliminated with the use of 2A peptide–based vectors. Particularly appealing aspects of this technology are the very small size of the 2A peptides and the fact that this cleavage event does not appear to be influenced by external factors, as is seen with internal promoters and IRES. In addition, we have effectively used the 2A peptide as a tag for protein identification using an anti-2A peptide antisera (data not shown). A potential drawback of this system is the possibility that the small, 2A tag left at the end of the N-terminal protein may affect protein function or contribute to the antigenicity of the proteins. However, we have not yet observed these problems in our studies.”
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to use thosea asigna virus 2A peptide in the AAV construct. The artisan would be motivated as the use of thosea asigna virus 2A peptide would decrease the problems associated with IRES sequences. The artisan would have a reasonable expectation of success as the artisan is merely known sequences in known constructs.
Claim(s) 121 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gao (Proceedings National Academy of Sciences USA ((vol 112) pages 14676-14681), Wantanbe (Gene Therapy (2010) 17, 1042–1051; doi:10.1038/gt.2010.87), Shu (HUMAN GENE THERAPY, VOLUME 27 NUMBER 9, pages 687-699as applied to claims 113-119, 122-131 above, and further in view of Zhang (J Gene Med 2005; 7: 354–365)
The teachings of Gao, Wantanbe and Shu are set forth above.
While the teachings of Gao, Wantanbe and Shu suggest AAV constructs encoding bevacizumab. They do not specifically teach the use of IL2 signal peptide.
However, Zhang teaches, “We chose IL-2 as the signal peptide sequence for amino acid substitution because it is commonly used in both commercial protein production and gene therapy research [22–28]” (pge 355, 2nd column, top)
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to use the IL-2 signal peptide to enhance secretion of bevacizumab. The artisan would be motivated to use IL2 signal peptide as Zhang teaches it is commonly used in both commercial protein production and gene therapy research. The artisan would have a reasonable expectation of success as the artisan is merely using known secretion signal peptides to enhance secretion of bevacizumab.
Summary
No claims are allowed.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Xie (Gynecologic Oncology 135 (2014) 325–332).
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/Steven Pohnert/ Primary Examiner, Art Unit 1683