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 .
Application Status
This action is written in response to applicant’s correspondence received on 05/02/2024. Claims 1-3, 10, 16, 19, 21-23, 25, 27-28, 30, 32-34, 39, 73-74, 82 are currently pending.
Information Disclosure Statement
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.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a CON of PCT/US2022/041084 filed on 08/22/2022, and claims priority to PRO 63/236,168 filed on 08/23/2021.
Drawings
The drawing is objected to because 37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG.”. In the current case, the view number for Figure 1 is preceded by the word "Fig." instead of the allcap abbreviation "FIG.".
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the terms Lucentis, Eylea, ATCC, Thermofisher Scientific, Fisher Scientific, GenScript, Regeneron, Abcam, Millipore Sigma, Invitrogen, Greiner Bio-One, CellStar, Nunc, ibidi USA, Farnworth-Munsell, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term 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 16 is objected to because of the following informalities: The recitation “a angiopoietin-1” should be “an angiopoietin-1”. Appropriate correction is required.
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.
Claims 1-3, 10, 16, 19, 21-23, 25, 27-28, 30, 32-34, 39, 73-74, 82 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.
Regarding claim 1, the recitation “(RTK)/Tie2” or “RTK/Tie2” in the claim and throughout the specification involves both the broad genus of a superfamily of “receptor tyrosine kinases (RTK)”, which encompasses numerous diverse structures with distinct functions, as evidenced by Du (Mol Cancer. 2018 Feb 19;17(1):58; Page 1, Background, 1st ¶). Tie2 is only a species of RTK and has alternative names such as Tunica interna Endothelial cell Kinase (TEK), TIE-2, or TIE2 receptor tyrosine kinase, as evidenced by Saharinen (Receptor Tyrosine Kinases: Family and Subfamilies. 2015 Mar 13:743–75; Page 743, first line; Page 746, Table 16.1). There is no clear definition of “(RTK)/Tie2” or “RTK/Tie2” in the specification, therefore, it is not clear whether the claim requires the inclusion of another RTK distinct from Tie2, with or without Tie2, or just Tie2.
Claims 2-3, 10, 16, 19, 21-23, 25, 27-28, 30, 32-34, 39, 73-74, 82 are also rejected for depending from the rejected claim 1 but failing to remedy the indefiniteness therein.
Claim 32 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 32 recites the limitation "the antibody or the fragment thereof". There is insufficient antecedent basis for this limitation in claim 1 upon which it depends. The recitation “an antibody or a fragment thereof” appears in claim 28.
Claim Interpretation
To advance prosecution, the recitations “(RTK)/Tie2” and “RTK/Tie2” are interpreted to encompass at least one embodiment wherein only Tie2 is required without any other RTK species, and the following office action is based on the at least one embodiment wherein only Tie2 is required.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 10, 28, 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Duerr (US20140017244A1, published on 01/16/2014), as evidenced by Kim (Eur J Immunol. 1999 29:2819-25), Yang (US8809017B2, issued on 08/19/2014), Auer (US20210139561A1, published on 05/13/2021), and Khan (EMBO Mol Med. 2021 Jul 7;13(7):e08253).
Regarding claim 1, Duerr (2014) teaches:
a “a nucleic acid encoding a bispecific antibody…” (Page 66, claim 13), i.e. a polynucleotide, “comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2” (Page 16, ¶[0246]; Front page, Abstract).
The “polynucleotide” is non-naturally occurring because it encodes antibodies comprising the engineered mutations I253 A, H310A and H435A (Duerr, Front page, Abstract) to reduce antibody viscosity (Duerr, page 2, ¶[0013]), based on the naturally occurring and highly conserved I253, H310, and H435 residues in immunoglobins, as evidenced by Kim (1999; Page 2819, right column, 2nd ¶, lines 3-5; Page 2823, under 3. Concluding remarks).
The polynucleotide comprises multiple expression cassettes because the recitation “a nucleic acid molecule encoding a heavy and/or light chain of a bispecific antibody…” (Duerr, Page 3, ¶[0037]) indicates that multiple polypeptides/chains that form a bispecific antibody require encoding by a single polynucleotide. It is known in the art that either single expression cassette, as evidenced by Yang’s teaching (2014; FIG. 1B, 4C), or multiple expression cassettes, as evidenced by Auer (2021; Title, Abstract) are used to encode multiple peptides of an anti-ANG2/VEGF bispecific antibody. Hence, at least some embodiments of Duerr encode the multiple chains of a bispecific antibody using multiple expression cassettes in a single polynucleotide, to avoid unpredictable random genome insertion of different expression cassettes which leads to "position effect variation" (Auer, Page 1, ¶[0005], line 11).
Duerr further teaches that both Ang1 and Ang2 bind to Tie2, and “ANG-1 and ANG-2 were originally identified in tissue culture experiments as agonist and antagonist, respectively” (Page 7, ¶[0142] last 8 lines). The bispecific antibody against VEGF and Ang2 (Ang-2, ANG2, or ANG-2) is designed to eliminate both from the eye (Page 3, ¶[0044], lines 17-21). This supports that anti-Ang2 antibody activates Tie2 in the eye by eliminating the antagonist Ang2, thereby providing more binding opportunities for the agonist Ang1 to induce functional activation of Tie2. Alternatively, using anti-Ang2 antibody as an activator of Tie2 (Ang2-binding Tie2 activating Ab, ABTAA) is illustrated by Khan (2021) in Figure 2E (Page 6-7). Hence, Duerr teaches a) a VEGF inhibitor, also teaches b) an activator of Tie2.
Regarding claim 2, Duerr further teaches “a nucleic acid molecule encoding a heavy and/or light chain of a bispecific antibody…” (Page 3, ¶[0037]). Since the two binding domains of a bispecific antibody are assembled by different heavy chains and light chains (Page 4, ¶[0074] - ¶[0076]), there are only two known strategies in the art to encode multiple peptides using a single polynucleotide. As evidenced by Yang (2014), one with ordinary skill in the art can design the polynucleotide to encode the separate polypeptides using IRES (Yang, Title, FIG. 1B, 4C) in a single expression cassette, or design the polynucleotide to encode a single contiguous polypeptide cleavable into multiple peptides using 2A self-cleaving peptides (Yang, Column 2, line 25).
Regarding claim 10, Duerr teaches a bispecific antibody against VEGF.
Regarding claims 28 and 30, Duerr further teaches an activator of Tie2 being the bispecific antibody against VEGF and Ang2, as evidenced by Khan (2021; Figure 2E, Ang2-binding Tie2-activating Antibody (ABTAA) enables tetrameric engagement and activation of Tie2).
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.
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 16, 19, 21-23, 25, 27, 32 are rejected under 35 U.S.C. 103 as being unpatentable over Duerr (2014), as evidenced by Kim (1999), in view of Wu (Sci Rep. 2016 Nov 14;6:36694), Daly (Sci Rep. 2018 Jan 11;8(1):505), Khan (2021), and further in view of Ellis (US200302 20250A1, published on 11/27/2003), Shimizu (US20180207293A1, published on 07/26/2018), Johnston (US20050137156A1, published on 06/23/2005), Giese (WO2020030672A1, published on 02/13/2021), & Dengl (US20170247441A1, published on 08/31/2017).
The teachings of Duerr have been discussed above and as applied to claims 1, 2, 10, 28, 30, and applied herein. Duerr does not teach:
“wherein the activator of the Tie2 comprises a angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), angiopoietin-3 (Ang-3), angiopoietin-4 (Ang-4), or a functional fragment of any one thereof”, (claim 16);
“wherein the functional fragment of the Ang-1 comprises or consists of a fibronectin-like domain (FLD)”, (claim 21);
“wherein the Ang-1 comprises or consists of a polypeptide sequence that is at least 70%, … identical to SEQ ID NO: 3”, (claim 19);
“wherein the FLD comprises or consists of a polypeptide sequence that is at least 70%, … identical to SEQ ID NO: 5”, (claim 22);
“wherein the FLD is fused to a soluble polypeptide”, (claim 23);
“wherein the soluble polypeptide comprises or consists of a polypeptide sequence that is at least 70%, … or more identical to SEQ ID NO: 2 or SEQ ID NO: 1”, (claim 25);
“wherein the activator of the Tie2 is at least 70%, … identical to SEQ ID NO: 6”, (claim 27);
“wherein the antibody or the fragment thereof comprises or consists of a polypeptide sequence that is at least 70%, … identical to any one of SEQ ID NOs: 139-141, a fragment thereof, or a combination thereof”, (claim 32).
However, Wu (Sci Rep. 2016 Nov 14;6:36694) teaches neoadjuvant therapy modalities combining Aflibercept (a VEGF trap) with BowAng1 (a recombinant Ang-1 variant) supplementation as an antiangiogenic therapy regimen to improve chemotherapy (paclitaxel, PTX) for triple negative breast cancers (Page 1, Title; Page 6, Figure 5). Wu does not teach the sequence make up of BowAng1.
However, Daly (2018) teaches that “BowAng1 and BowAng2 contain the Ang1 or Ang2 fibrinogen domain …”, i.e. FLD (Page 8, line 8).
None of Duerr, Kim, Wu, or Daly teach the above limitations c-h.
Ellis (2003) teaches limitation c, Shimizu (2018) teaches limitation d, Johnston (2005) teaches limitation e & f, Giese (2021) teaches limitation g, and Dengl (2017) teaches limitation h.
Regarding claim 16, Daly further teaches that “wherein the activator of the Tie2 comprises a functional fragment of angiopoietin-1 (Ang-1)”.
Regarding claim 21, Daly further teaches that “wherein the functional fragment of the Ang-1 comprises or consists of a fibronectin-like domain (FLD)”.
Regarding claim 19, Ellis (2003) teaches an angiopoietin-1 polypeptide (NCBI GenBank database Accession Number: AAB50557) with a sequence set forth in SEQ ID NO: 13, which is 100% identity match with the claimed SEQ ID NO: 3, see alignments below:
Query: Instant SEQ ID NO: 3, Sbjct: SEQ ID NO: 13 of Ellis
PNG
media_image1.png
743
882
media_image1.png
Greyscale
Regarding claim 22, Shimizu (US20180207293A1, published on 07/26/2018) teaches an Angiopoietin-1 Protein-Ala-His with a sequence set forth in SEQ ID NO: 59 (300AA) based on Sequence Listing, and comprises 100% (243/243AA) of the claimed FLD sequence of SEQ ID NO: 5 (243AA), see alignment below:
Query: Instant SEQ ID NO: 5, Sbjct: SEQ ID NO: 59 of Shimizu
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media_image2.png
440
873
media_image2.png
Greyscale
Regarding claim 23, Johnston (US20050137156A1, published on 06/23/2005) teaches that “any protein fused to COMP”, and that COMP is a small polypeptide of (46 amino acids) which is “a highly soluble … domain …” (Page 37, last line) used “to enhance solubility” (Page 12, lines 19, 21, 25).
Regarding claim 25, Johnston (2005) further teaches a SEQ ID NO: 30, which is COMP (45AA): DLAPQMLRELQETNAALQDVRELLRQQVKEITFLKNTVMECDACG, and comprises 100% of the 45AA claimed SEQ ID NO: 1, DLAPQMLRELQETNAALQDVRELLRQQVKEITFLKNTVMECDACG see alignment below:
Query: Instant SEQ ID NO: 1, Sbjct: SEQ ID NO: 30 of Johnston
PNG
media_image3.png
132
847
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Greyscale
Regarding claim 27, Giese (WO2020030672A1, published on 02/13/2021) teaches a SEQ ID NO: 98, a 288AA polypeptide encoded by a hCOMP-Ang1 CDS (Page 76, Table 1), and it comprises 98% identity (281/288AA) of the 288AA claimed SEQ ID NO: 1, see alignment below:
Query: Instant SEQ ID NO: 6, Sbjct: SEQ ID NO: 98 of Giese
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433
842
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Greyscale
Regarding claim 32, claim interpretation: based on the recitation “the antibody or the fragment thereof”, it is interpreted that claim 32 is intended to depend from 28. Dengl (US20170247441A1, published on 08/31/2017) teaches nucleic acids encoding antibody or fragments thereof (Page 5, ¶[0062]) with amino acid sequences set forth in SEQ ID NO: 1, Ang2 LC10 VH, which has 100% identity match with the claimed SEQ ID NO: 139, and SEQ ID NO: 6, Ang2 LC10 VL, which has 100% identity match with the claimed SEQ ID NO: 140, see alignments below:
Query: Instant SEQ ID NO: 139, Sbjct: SEQ ID NO: 1 of Dengl
PNG
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284
857
media_image5.png
Greyscale
Query: Instant SEQ ID NO: 140, Sbjct: SEQ ID NO: 6 of Dengl
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211
856
media_image6.png
Greyscale
It would have been obvious to persons having ordinary skills in the art (PHOSITAs) before the effective filing date of the claimed invention to have modified the non-naturally occurring polynucleotide encoding a bispecific antibody against VEGF and Ang2 taught by Duerr (2014) to explore swapping the anti-Ang2 antibody components with the direct agonist for Tie2, BowAng1, or equivalents in the same class of agonists, taught by Wu (2016) and Daly (2018), or substituting the antibody sequences based on known arts taught by Dengl (2017). It would have merely amounted to a simple substitution of prior art elements, taught by Ellis (2003), Shimizu (2018), Johnston (2005), Giese (2021), and Dangl (2017) according to known methods to yield predictable results. One would have been motivated to do so because Khan (2021) teaches that BowAng1 and anti-Ang2 antibodies both activate Tie2 (Page 6, FIG. 2E & 2F), and comparing the two methods with various known sequence elements helps identify the optimal therapeutic compound to achieve optimal efficacy. One would have reasonable expectation of success because the known methods work through the same two-pronged mechanism by coupling anti-VEGF with augmenting Tie2 signaling.
Claims 3 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Duerr (2014), as evidenced by Kim (1999), in view of Yang (2014; see full citation above in §102 above).
The teachings of Duerr have been discussed above and as applied to claims 1, 2, 10, 16, 19, 21-23, 25, 27, 28, 30, 32, and applied herein. Duerr does not teach the limitations “wherein the contiguous polypeptide comprises a protease cleavable sequence, a Furin cleavable sequence, or a self-cleaving polypeptide sequence”, or “wherein the one or more expression cassettes comprise one or more promoters, one or more internal ribosome entry sites (IRES), or both”.
Yang (2014) teaches strategies to produce bispecific or monospecific antibodies using multicistronic vectors (FIGs. 1, 4, 9A, 13, 19) and describes expressing the heavy chain (HC) or light chain (LC) in a multi-vector expression system as a common method (Column 1, lines 39-52). To improve expression efficiency and yield, internal ribosome entry site (IRES) and 2A peptide provides alternative approaches for co-expression of multiple genes (Column 2, lines 16-27).
Regarding claim 3, Yang (2014) further teaches that “The 2A self-processing cleavage occurs between the last 2 amino acids at the C terminus of the 2A peptide…” (Column 31, lines 29-31). Hence, Yang teaches “a self-cleaving polypeptide sequence”.
Regarding claim 39, Yang (2014) teaches a multi-vector expression system (Column 1, lines 39-52), wherein the one or more expression cassettes comprise one or more promoters, one or more internal ribosome entry sites (IRES), or both (see vector schemes in FIG. 4B and 4C).
It would have been obvious to PHOSITAs before the effective filing date of the claimed invention to have modified the non-naturally occurring polynucleotide encoding a bispecific antibody against VEGF and Ang2 taught by Duerr (2014) to explore constructing multi-cistronic vectors, taught by Yang (2014) by substituting the polynucleotide structures used by Duerr. It would have merely amounted to a simple substitution of prior art elements, taught by Yang (2014) and Duerr (2014) according to known methods to yield predictable results. One would have been motivated to do so because comparing different vector construct designs with various known sequence elements helps identify the optimal therapeutic compound to achieve optimal efficacy. One would have reasonable expectation of success because these known methods work in similar fashion to enable multi-component delivery to producer cells.
Claims 33 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Duerr (2014), as evidenced by Kim (1999), in view of Reich (US7994305B2, issued on 08/08/2011), further in view of Khan (2021; see full citation above in §102 above).
The teachings of Duerr have been discussed above and as applied to claims 1, 2, 3, 10, 16, 19, 21-23, 25, 27, 28, 30, 32, 39, and applied herein. Duerr does not teach the limitations “wherein the activator of the Tie2 comprises an inhibitory RNA” or “wherein the inhibitory RNA comprises a shRNA, siRNA, miRNA, or a combination thereof”.
However, Reich (2011) teaches an AAV vector expressing an siRNA, an inhibitory RNA, targeting Ang2 mRNA for antiangiogenic therapy (Reich, Claim 1). Since Khan (2021) teaches that “Ang2 competes for the same binding site on Tie2 as Ang1 explaining its antagonistic effect on Ang1-induced Tie2 phosphorylation” (Page 7, Figure 2E, legends), reducing the levels of Ang-2 by siRNA knockdown serves the same function of activating Tie2 by improving Ang-1 binding to Tie2 using neutralizing antibodies, such as the ABTAA (Khan, Figure 2E). Hence, Reich teaches an activator of Tie2 comprising an inhibitory RNA, e.g. an siRNA.
Regarding claims 33 and 34, it would have been obvious to PHOSITAs before the effective filing date of the claimed invention to have modified the non-naturally occurring polynucleotide encoding a bispecific antibody against VEGF and Ang2 taught by Duerr (2014) to explore swapping the anti-Ang2 antibody components with the inhibitory RNA for Ang2, an siRNA, or equivalents in the same class of agonists, taught by Reich (2011). It would have merely amounted to a simple substitution of prior art elements, taught by Duerr (2014) and Reich (2011) in view of Khan (2021), according to known methods to yield predictable results. One would have been motivated to do so because of in vivo impact observed in mice by Reich, and comparing the two methods with various known inhibition methods for Ang2 helps identify the optimal therapeutic compound to achieve optimal efficacy. One would have reasonable expectation of success because the known methods work through the same two-pronged mechanism by coupling anti-VEGF with augmenting Tie2 signaling.
Claims 73, 74 and 82 are rejected under 35 U.S.C. 103 as being unpatentable over Duerr (2014), as evidenced by Kim (1999), in view of Yan (WO2017205014A1, published on 11/30/2017).
The teachings of Duerr have been discussed above and as applied to claims 1, 2, 3, 10, 16, 19, 21-23, 25, 27, 28, 30, 32-34, 39, and applied herein. Duerr does not teach the limitations “A viral vector comprising the non-naturally occurring polynucleotide of claim 1”, “wherein the viral vector is an adeno- associated viral (AAV) scAAV vector”, or “a method for treating a disease or a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the non-naturally occurring polynucleotide of claim 1…”.
However, Yan (2017) teaches one or more nucleic acids, i.e. polynucleotides, encoding engineered or altered (e.g. non-naturally occurring humanized antibodies, built by combining parts from different species in a laboratory, Claim 1) antibodies or mixtures of antibodies (Claim 66; Page 68-90, Examples 1-4), i.e. non-naturally occurring polynucleotide, comprising one or more expression cassettes for expressing: a) a VEGF antibody, i.e. inhibitor for VEGF; and b) an Ang2 antibody (Page 115, claim 48 (r)). Yan further teaches bispecific antibodies (FIG. 2, Antibody 3), viral vectors (Claim 69) and AAV vectors (Claim 70).
Regarding claims 73 and 74, it would have been obvious to PHOSITAs before the effective filing date of the claimed invention to have modified the non-naturally occurring polynucleotide encoding a bispecific antibody against VEGF and Ang2 taught by Duerr (2014) to explore swapping the protein components with the viral vectors as delivery vehicles for the non-naturally occurring polynucleotide taught by Yan (2017). It would have merely amounted to a simple substitution of prior art elements, taught by Duerr (2014) and Yan (2017) according to known methods to yield predictable results. One would have been motivated to do so because of protein and nucleic acid-based therapeutics are commonly explored and compared side-by-side as alternatives, as demonstrated by Yan (Claim 1 vs claims 66-70). Comparing the two delivery formats and strategies helps identify the optimal therapy to achieve optimal efficacy. One would have reasonable expectation of success because the known antibody therapy and gene therapy methods share the same two-pronged targeting mechanism by coupling anti-VEGF with activating Tie2 signaling.
Regarding claim 82, Yan (2017) further teaches a method for treating a disease or a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the non-naturally occurring polynucleotide of claim 1 (Claims 79-81). The recitation “thereby…” is an intended use or intended outcome statement, therefore carrying no patentability weight because it does not constitute an active step that distinguishes from methods comprising the same known steps capable of producing the same results.
Subject Matter Eligibility Analysis
Claim 1 recites a non-naturally occurring polynucleotide, which is a composition of matter falling within one of the four statutory categories under 35 U.S.C. § 101. Yes, claim 1 satisfies Step 1.
Step 2A, Prong One: Claim 1 recites a polynucleotide comprising one or more expression cassettes for expressing (a) a VEGF inhibitor and (b) a Tie2 or an activator of Tie2. Yes, claim 1 recites a natural phenomenon. Does claim 1 have markedly different characteristics from any product of nature? Yes. Because there is no naturally occurring polynucleotide that contains, on a single contiguous molecule, coding sequence for both a VEGF-pathway modulator and an Ang/Tie2-pathway modulator. The genes encoding known VEGF inhibitors and pathway components (e.g., VEGFA, FLT1) reside on chromosomes distinct from those encoding angiopoietin/Tie2-pathway genes (ANGPT1, TEK), and no natural biological process produces a single isolated nucleic acid molecule spanning these unrelated loci as claimed. Because the combination of (a) and (b) on one polynucleotide is the structural feature that defines claim 1, and because no such combined molecule exists in nature, claim 1 as a whole has markedly different characteristics from any product of nature. No, Claim 1 does not recite a “product of nature” judiciary exception (JE), and analysis does not need proceed to Step 2A Prong Two or Step 2B.
Conclusion: Claim 1 is eligible under 35 U.S.C. § 101.
Dependent claims: Each dependent claim (e.g., claims 2, 3, 10, 16, 19, 21, 22, 23, 25, 27, 28, 30, 32, 33, 34, 39, 73, 74, 82) incorporates by reference the full scope of claim 1, including the requirement that both (a) a VEGF inhibitor and (b) an RTK/Tie2 or activator of RTK/Tie2 be encoded on the same non-naturally occurring polynucleotide. Narrowing an individual component of (a) or (b) to a specific structural species does not remove the claim from the combination that renders claim 1 eligible, because the other required element remains present on the same molecule. The eligibility inquiry is directed to the claim as a whole, not to whether each individual claimed component independently differs from its natural counterpart, see MPEP 2106.04(c). Accordingly, no dependent claim reintroduces the product-of-nature exception, and each claim is eligible under § 101 for the same reason as claim 1.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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