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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 59-76, drawn to compositions comprising polynucleotides and recombinant adeno-associated virus particles comprising the polynucleotides and species 1, claims 59-69, drawn to compositions comprising the polynucleotide of claim 59 in the reply filed on December 17, 2025 is acknowledged.
Claims 77-78 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Claims 70-76 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 17, 2025.
Claims 59-69 are being examined on the merits.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on August 29, 2023; September 16, 2024; July 23, 2025; September 2, 2025; and December 17, 2025 are is in compliance with the provisions of 37 CFR 1.97 and are being considered by the examiner.
Applicant is reminded that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objections to the Specification
The use of the terms BLAST, BLAST-2, ALIGN, NEEDLE, and DNASTAR in Para. [0027], Eylea and Lucentis in Para. [0053], and TransT-VirunGEN in Para. [00155], which are trade names or a marks used in commerce, has been noted in this application. Additionally, Para. [00133] contains a list of ocular therapeutic agents of which some (at least Eylea and Lucentis as previously mentioned) are likely trade names or marks. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 64 is objected to because of the following informalities: instantly recited SEQ ID NO: 14 and instantly recited SEQ ID NO: 17 appear to share 100% sequence identity (See search results dated 01/08/2026, seq 14 .rapbm file, result 1, duplicates). Appropriate correction is required.
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.
Claims 59-60 and 65-69 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 59 encompasses a genus of codon-optimized nucleic acid sequences encoding a genus of proteins comprising amino acids sequences having at least 99% homology to SEQ ID NO:s 1-12 which encode VEGF inhibitors while the specification only discloses a fixed number of species of said codon-optimized nucleic acid sequences encoding a fixed number of proteins comprising amino acids sequences which encode a VEGF inhibitor.
Dependent claim 60 encompasses a genus of codon-optimized nucleic acid sequences encoding a genus of proteins comprising an amino acid sequence of SEQ ID NO:s 1-12 which encode VEGF inhibitors while the specification only discloses a fixed number of species of said codon-optimized nucleic acid sequences encoding a fixed number of proteins comprising amino acids sequences which encode a VEGF inhibitor. The instant claims recite “an amino acid sequence of SEQ ID NOs: 1-12.” According to Technology Center 1600 procedure the examiner is instructed to interpret this type of claim language broadly: Claim language such as claim 60 encompasses amino acids that comprise the full-length sequence of SEQ ID NOs: 1-12 or any portion of SEQ ID NOs: 1-12. If the claim were amended to recite “…wherein the codon-optimized nucleic acid sequence encodes a protein comprising the amino acid sequence of SEQ ID NOs: 1-12” the examiner would interpret the claims to encompass only amino acids that comprise the full length of SEQ ID NOs: 1-12, with or without additional nucleotides at either or both ends.
Dependent claim 65-69 encompasses a genus of regulatory elements for use with the polynucleotides.
Under the new Written Description Guidelines for antigen binding molecules, the Examiner is directed to determine whether one skilled in the art would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination: on 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. 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 re-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.
ACTUAL REDUCTION TO PRACTICE
In regard to claim 59 encompassing a genus of codon-optimized nucleic acid sequences encoding a genus of proteins comprising amino acids sequences having at least 99% homology to SEQ ID NO:s 1-12 which encode a genus of VEGF inhibitors, the specification shows five embodiments for said codon-optimized nucleic acid sequences, SEQ ID NOs 14-18, (Pgs. 50-54). Although Applicant recites wherein the claimed codon-optimized nucleic acid sequences encode a genus of amino acid sequences which encode a genus of VEGF inhibitors (SEQ ID NOs: 1-12), the aforementioned embodiments of codon-optimized nucleic acid sequences SEQ ID NOs 14-18 encode a single VEGF inhibitor, instant SEQ ID NO: 1. (See Table 2, Examples 4-7).
In regard to dependent claim 60 encompassing a genus of codon-optimized nucleic acid sequences encoding a genus of proteins comprising amino acids sequences of SEQ ID NO:s 1-12 which encode a genus of VEGF inhibitors, the specification shows five embodiments for said codon-optimized nucleic acid sequences, SEQ ID NOs 14-18, (Pgs. 50-54). Although Applicant recites wherein the claimed codon-optimized nucleic acid sequences encode a genus of amino acid sequences which encode VEGF inhibitors (SEQ ID NOs: 1-12), the aforementioned embodiments of codon-optimized nucleic acid sequences SEQ ID NOs 14-18 encode a single VEGF inhibitor, instant SEQ ID NO: 1. (See Table 2, Examples 4-7).
Therefore, as stated above, it appears that Applicant was only in possession of a limited number of codon-optimized nucleic acid sequences which encode a single VEGF inhibitor.
DISCLOSURE OF STRUCTURE
The Applicant has provided sequence listings of SEQ ID NOs for five embodiments of the codon-optimized nucleic acid sequences (SEQ ID NOs: 14-18) which encode amino acid sequences for a single VEGF inhibitor (SEQ ID NO: 1). Certainly, with the help of a computer, a skilled artisan could identify the framework and all of the CDRs which encode VEGF inhibitors, the related amino acid sequences, and the codon-optimized nucleic acids encoding said amino acids encoding VEGF inhibitors. However, neither the specification nor the art indicate a relationship between the structure of the claimed genus of codon-optimized nucleic acid sequences encoding the claimed genus of VEGF inhibitors and the ability to produce functional VEGF inhibitors.
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
As mentioned above, the complete codon-optimized nucleic acid sequences corresponding to the SEQ ID NO of a specific amino acid sequence which encodes a specific VEGF inhibitor are provided.
Accordingly, if the skilled artisan sought to generate the claimed genus of codon-optimized nucleic acids, they would first need to know which nucleic acid sequences encoding amino acids could be chosen and still be able to predictably produce a VEGF inhibitor. Hence, based on the new written description guidelines, the Examiner should conclude that the applicant was not in possession of the claimed genus of codon-optimized nucleic acids beyond the sequences described in the specification.
The breadth of the claims encompass a genus of codon-optimized nucleic acid sequences comprising any protein having 99% homology to amino acid sequences SEQ ID NOs 1-12 which encode a protein capable of functioning as a VEGF inhibitor. The present specification provides no guidance nor description to any rational in choosing the sequences that were identified; therefore the skilled artisan would not know what rational approach to take to make modifications with any predictable outcome on generating a VEGF inhibitor. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of a larger genus of codon-optimized nucleic acids related to those comprising these individual species. Otherwise, the Written Description guidelines suggest that the applicant is entitled to only the species specifically recited as having this activity. Moreover, 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, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
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.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of making the claimed invention is not well established. Although the screening of biological ligands is routine and conventional, one of skill in the art would neither expect nor predict the appropriate functioning of the VEGF inhibitor proteins produced according to the claimed genus of codon-optimized nucleic acids as broadly as is claimed. 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, 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. While CDR mutations might be expected to alter antigen binding of an antibody, framework mutations can also have an effect. Panka et al. (Proceedings of the National Academy of Sciences USA, Vol., 85, 1988) teach that a single amino acid difference in a framework residue at the boundary with CDR3 was responsible for the decreased affinity of an anti-digoxin antibody (Pg. 3083, Column 1, Paragraph, first partial). Similarly, in regard to the VEGF binding affinity, Muller et al . (1998, VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure of the complex at 2.4 Å resolution and mutational analysis of the interface. Structure, 6(9), 1153-1167) teaches that single amino acid alterations at particular positions of the Fab fragment of a humanized antibody can produce widely variable alterations in VEGF binding affinity, including large decreases in binding affinity associated with amino acid alterations at particular positions within heavy chain CDRs and a single position within light chain CDRs (Pg. 1159, right col., 2nd para.).
Applicant has claimed a genus of nucleic acid sequences encoding VEGF inhibitors, yet the specification has only managed to identify very specific nucleic acid sequences that can be used as a specific VEGF inhibitor. Independent of how these specific sequences were arrived upon by Applicant, a protein encoding a VEGF inhibitor cannot have any position modified and predictably produce functional inhibitor. Because Applicant has no manner a priori to predict which codon-optimized nucleic acid sequences can be modified and used to encode an amino acid sequence encoding a functioning VEGF inhibitor, the genus of codon-optimized nucleic acids claimed by Applicant cannot be predictably made or used by the ordinary artisan.
Not knowing, absent further experimentation and screening, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect structure and function, leads to one having no predictability or expectation of success for the function of any given VEGF inhibitor. Such random experimentation to identify at a later time what structure or variant or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation. Furthermore, functionally defined genus claims (i.e., a target-specific inhibitor) 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).
CONCLUSION
Therefore, the examiner concludes that there is insufficient written description of the instantly claimed genus. Specifically, there is limited description of the structure-function relationship between the claimed genus of codon-optimized nucleic acid sequences and their ability to produce the claimed genus of VEGF inhibitors, and the Examiner further concludes a skilled artisan would find the specification inadequately describes the amino acids encoding VEGF inhibitors encompassed by the claimed genus of codon-optimized nucleic acid sequences.
Claim Rejections - 35 USC § 112(b)
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 59-69 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.
With regard to claims 59-61, claim 59 and claims 60-61 which depend from claim 59, recite the limitation "the codon-optimized nucleic acid sequence encodes a protein…". There is insufficient antecedent basis for this limitation in the claim as the prior recitation is to a “codon-optimized nucleic acid sequence encoding a VEGF inhibitor”. As instantly claimed, there is a single recitation of a codon-optimized nucleic acid sequence which encodes both “a VEGF inhibitor” and “a protein” and it is unclear whether the recitation of “a protein” is intended to refer to “a VEGF inhibitor” or to another protein. Appropriate correction is required. It is recommended that Applicant amend to maintain consistent language of a codon-optimized nucleic acid sequence which encodes a VEGF inhibitor.
Claims 63-69 are similarly rejected for incorporating the limitations of a rejected claim while failing to correct the deficiencies based on their dependency from claim 59.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 60 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. As stated above, the instant claims recite “an amino acid sequence of SEQ ID NOs: 1-12.” According to Technology Center 1600 procedure the examiner is instructed to interpret this type of claim language broadly: Claim language such as claim 60 encompasses amino acids that comprise the full-length sequence of SEQ ID NOs: 1-12 or any portion of SEQ ID NOs: 1-12. As instantly claimed, this claim encompasses any amino acid comprising any dinucleotide or larger oligonucleotide which is a portion of SEQ ID NOs: 1-12 and therefore it not further limiting. If the claim were amended to recite “…wherein the codon-optimized nucleic acid sequence encodes a protein comprising the amino acid sequence of SEQ ID NOs: 1-12” the examiner would interpret the claims to encompass only amino acids that comprise the full length of SEQ ID NOs: 1-12, with or without additional nucleotides at either or both ends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 59-62, 64, and 66-69 are rejected under 35 U.S.C. 103 as being unpatentable over Danos et al. (WO 2019079494, found in IDS dated 09/16/2025, hereafter “Danos”).
With regard to claims 59-61, Danos teaches a composition for the delivery of human post-translationally modified VEGF-Trap (Para. [0001]) via use of a viral vector or DNA expression construct encoding a VEGF-Trap protein (Paras. [0007], [0076]). Danos teaches embodiments wherein the VEGF-Trap comprises the amino acid sequence of aflibercept (a VEGF inhibitor) comprising SEQ ID NO: 1 and use of codon-optimized nucleotide sequences encoding aflibercept/SEQ ID NO: 1 (Paras. [0009], [0012], [0078], [0080], [0094], [0097]). SEQ ID NO: 1 as taught by Danos shares 100% similarity to instantly claimed SEQ ID NO:1 (See search results dated 01/08/2026, SEQ ID NO: 1 .rapbm file, result 1 duplicates, entry for US20210010025).
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Danos further teaches and that the expression construct encoding aflibercept/SEQ ID NO: 1 can be controlled by expression control elements, including promoters (Para. [0010]) and that the expression construct encoding the VEGF-Trap protein is operably linked to said expression control sequences (Para. [0013], See also [106], [0109]. This is considered to reasonably read on a polynucleotide comprising a sequence operably linked to a promoter wherein the sequence comprises a codon-optimized nucleic acid sequence encoding a VEGF inhibitor comprising the amino acid sequence of instantly claimed SEQ ID NO: 1 (See also section 5.2).
Additionally, Danos teaches use of expression vectors which can be recombinant adeno-associated viral vectors (rAAV) comprising a capsid (Para. [0010]) and constructs comprising an AAV vector and an expression cassette comprising a polynucleotide encoding a VEGF inhibitor operably linked to a promoter (Para. [0013]). Further, Danos teaches a host cell comprising an expression cassette comprising a polynucleotide encoding a VEGF inhibitor operably linked to expression control elements (i.e., a promoter) and an expression cassette which encodes an AAV rep and capsid protein operably linked to expression control elements (i.e., promoters) (See embodiments 60 and 61). This is considered to reasonably read on a polynucleotide comprising a first sequence encoding an AAV capsid protein and a second sequence encoding an AAV rep protein. Danos teaches that these polynucleotides encoding the AAV rep and capsid proteins are operably linked to expression control elements, which Danos indicates can be promoters (See section 5.2.3) and it would be readily apparent to one having ordinary skill in the art, based on the teachings of Danos, to optimize the polynucleotide comprising the sequences encoding the AAV capsid protein and AAV rep protein such that each sequence is operably linked to a promoter.
With regard to claim 62, Danos teaches a codon-optimized nucleic acid sequence encoding aflibercept comprising SEQ ID NO: 2 (see Table 1). Instantly claimed SEQ ID NO: 13 comprises 48 CpG nucleotides. Danos’s SEQ ID NO: 2 comprises 62 CpG dinucleotides and therefore is considered to reasonably read on comprising an altered number of CpG dinucleotides from instantly claimed SEQ ID NO: 13.
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With regard to claim 64, the instant claims recite “the third sequence comprises a sequence of SEQ ID NOs 14-18.” According to Technology Center 1600 procedure the examiner is instructed to interpret this type of claim language broadly: Claim language such as claim 64 encompasses nucleic acids that comprise the full-length sequence of SEQ ID NOs: 14-18 or any portion of SEQ ID NOs: 14-18. Therefore, this claim is taught by any nucleic acid comprising any dinucleotide or larger oligonucleotide which is a portion of SEQ ID NOs:14-18 and thus is taught by SEQ ID NO: 2 of Danos.
If claim 64 were amended to recite the third sequence comprises the sequence of SEQ ID NOs 14-18.”, the examiner would interpret the claims to encompass only nucleic acids that comprise the full length of SEQ ID NOs: 14-18, with or without additional nucleotides at either or both ends. Such language appears to be free of the prior art.
With regard to claims 66 and 67, Danos teaches that the promoter for the expression construct encoding aflibercept can be a tissue specific promoter such as an RPE promoter, which is considered to reasonably read on an eye-specific promoter and provides an exemplary embodiment of an RPE65 promoter (Para. [0010], line 16; Para. [0107], lines 8-9, Paras. [0109], [0133]).
With regard to claim 68, Danos teaches that the construct can comprise expression control elements such as an hGH poly(A) signal (Para. [0011]). The example construct provided in Para. [0141] indicates that the poly(A) sequence is at the 3’ end (see also Figs 5A-F).
With regard to claim 69, Danos teaches that the expression construct encoding a VEGF-Trap protein which is operably linked to regulatory sequences controlling it’s expression is “flanked” by AAV inverted terminal repeats (Paras. [0065], [0112], [0145], Figs 5A-F).
Claim 63 is rejected under 35 U.S.C. 103 as being unpatentable over Danos as applied to claim 59, 61, and 62 above, and further in view of Kirn et al. (US 20200282077, priority date of 11/26/2018, hereafter “Kirn”) and Scheule (2000, The role of CpG motifs in immunostimulation and gene therapy. Ad. Drug Deliv. Rev., 44(2-3), 119-134).
With regard to claim 63, as detailed above, Danos teaches a composition comprising a first polynucleotide comprising sequences encoding AAV capsid and rep proteins operably linked to promoters and second polynucleotide comprising a codon-optimized nucleotide sequence encoding a VEGF inhibitor operably linked to a promoter which encodes a protein comprising an amino acid sequence of instantly claimed SEQ ID NO: 1.
While Danos teaches codon-optimization of the nucleic acid sequence encoding a VEGF inhibitor and an embodiment of SEQ ID NO: 2 which contains 62 CpG dinucleotides, Danos also teaches a condon-optimized consensus sequence (SEQ ID NO:3, see Table 1) which encodes an protein comprising SEQ ID NO: 1, indicating that various codon-optimized nucleic acid sequences encoding a VEGF inhibitor could be used in the composition.
Kirn teaches a nucleic acid sequence encoding a VEGF inhibitor (aflibercept) comprising SEQ ID NO: 65 (claim 1) which is codon-optimized (Paras. [0226], [0227]). Kirn’s SEQ ID NO: 65 comprises 52 CpG dinucleotides.
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Kirn further teaches that SEQ ID NO: 65 encodes an amino acid comprising amino acids 27-458 of Kirn’s SEQ ID NO: 66 (Para. [0277]). Amino acids 27-458 of SEQ ID NO: 66 as taught by Kirn are 100% identical to instantly claimed SEQ ID NO: 1. Thus, SEQ ID NO: 65 as taught by Kirn is considered to encode the same protein as instantly claimed SEQ ID NO: 1.
Scheule teaches that DNA sequences containing CpGs are linked to stimulation of the immune system which is counterproductive in the field of gene therapy (Pg. 120, left col., 1st para.) and that in gene therapy applications, minimizing CpG-mediated effects and thereby immune stimulation is desirable (Pg. 123, left col. 1st full para.). Scheule further teaches that, in gene therapy, stimulatory CpG motifs induce cytokine expression and have undesired effects on expression and toxicity (Pg. 127, left col., 1st para.) and that alterations to reduce the number of CpG sequences is the most practical method of reducing immunostimulation (Pg. 129, right col., 2nd para.).
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Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the claimed invention, to choose the codon-optimized nucleic acid sequence comprising SEQ ID NO: 65 which encodes a VEGF inhibitor and comprises less than 60 CpG dinucleotides as taught by Kirn for use in Danos’ composition comprising a first polynucleotide comprising sequences encoding AAV capsid and rep proteins operably linked to promoters and second polynucleotide comprising a codon-optimized nucleotide sequence encoding a VEGF inhibitor operably linked to a promoter which encodes a protein comprising an amino acid sequence of instantly claimed SEQ ID NO: 1, particularly in view of Scheule. A skilled artisan would have recognized, based on Danos, that one could choose various codon-optimized nucleic acid sequences encoding VEGF inhibitors having the amino acid sequence of SEQ ID NO:1 for use in the composition with a reasonable expectation of success and with the predictable outcome of generating a composition comprising a codon-optimized nucleic acid sequence having less than 60 CpG dinucleotides which encodes a protein comprising an amino acid sequence of SEQ ID NO: 1. Further, a skilled artisan would have recognized based on Scheule that choosing Kirn’s nucleic acid sequence which encodes a VEGF inhibitor having the amino acid sequence of SEQ ID NO:1, which has fewer CpG dinucleotides compared to SEQ ID NO:2 as taught by Danos, would provide the benefit of reducing host immune response which is critical for effective use of compositions in gene therapy applications.
Claim 65 is rejected under 35 U.S.C. 103 as being unpatentable over Danos as applied to claim 59 above in view of Aponte-Ubillus et al. (2018). Molecular design for recombinant adeno-associated virus (rAAV) vector production. Applied Microbio. and Biotech., 102(3), 1045-1054, hereafter “Aponte-Ubillus”).
With regard to claim 65, as detailed above, Danos teaches a composition comprising a first polynucleotide comprising sequences encoding AAV capsid and rep proteins operably linked to promoters and second polynucleotide comprising a codon-optimized nucleotide sequence encoding a VEGF inhibitor operably linked to a promoter which encodes a protein comprising an amino acid sequence of instantly claimed SEQ ID NO: 1.
Danos teaches that baculovirus expression systems in insect cells may be used to produce AAV vectors and cites Aponte-Ubillus (Para [0149]) but is silent as to the use of p10 or polh promoters.
Aponte-Ubillus teaches various designs for recombinant AAV production (Abstract, whole document) including baculovirus expression systems for use in insect cells (Pg. 1048-1051, Insect cell-baculovirus expression system). Aponte-Ubillus teaches that use of baculovirus specific polh promoters in insect systems is required to produce AAV vectors which are comparable to those produced in mammalian cells (Pg. 1050, see also Fig. 3c) and that use of insect expression systems leads to high per cell and volumetric productivity of AAVs (Pg. 1051, left col., 3rd para.) and that insect cells can grow in suspension and are easily adapted to large-scale production (Pg. 1049, left col.).
Therefore, it would have been obvious to one having ordinary skill in the art, before the effective filing date of the instant invention to choose polh promoters for use in the first polynucleotide comprising sequences encoding AAV capsid and rep proteins as taught by Danos with a reasonable expectation of success. A skilled artisan would have chosen use of polh promoters as they are required for generating AAV vectors using insect baculovirus expression systems and use of insect baculovirus systems would maximize production of AAVs.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631