Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of Application, Amendments, and/or Claims
2. The Amendment filed on 04 September 2025 has been entered in full. Claims 1, 68, 80-81, 88, 91, 94 and 100 have been amended, claims 69, 78-79, 87, 90, 92-93 and 95-96 have been canceled, and claims 102-103 have been added. Newly added claims 102-103 will be examined as they fit under the rubric of the elected invention. Therefore, claims 1, 62-64, 67-68, 80-81, 88-89, 91, 94 and 98-103 are pending and the subject of this Office Action.
3. For clarity of record, the previous Office action (mailed 04 June 2025) set forth the rational to support the rejection of claims 98-101 under 35 U.S.C. 103(a) at pg. 7 ¶ 19, and was addressed by Applicant at pp. 9-10 of the response (filed 04 September 2025). The listing of rejected claims in the statement at pg. 6 ¶ 16 was an obvious typographical error, containing cancelled claims, as the claims were indicated as rejected at the summary of the Office action, and indicated as rejected on the PTOL-326.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 05 September 2025 has been considered by the examiner.
Withdrawn Objections and/or Rejections
5. The rejection of claims 1, 62-68, 78-79, 81, 85 and 87 under 35 U.S.C. 103 as set forth at pp. 4-6 of the previous Office action (mailed 04 June 2025) is withdrawn in view of Applicant’s amendment of claim 1 and 81, and cancelation of claims 78-79 and 87 (filed 04 September 2025).
6. The rejection of claims 69, 78-79, 87, 90, 92-93 and 95-96 under 35 U.S.C. 103 as set forth at pp. 6-8 of the previous Office action (mailed 04 June 2025) is moot in view of Applicant’s cancelation of said claims (filed 04 September 2025).
New and/or Maintained Objections and/or Rejections
Claim Rejections - 35 USC § 103
7. 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 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.
8. 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.
9. 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.
10. 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.
11. Claims 1, 62-68, 78-79, 81, 85 and 87 remain rejected under 35 U.S.C. 103 as being unpatentable over Mabry et al. (mAbs 2(1):20-34, published 2010; cited by Applicant), and further in view of Wiegand et al. (U.S. Pat. No. 9,265,827; priority to 2013), Serruys et al. (Int. J. Cardiovasc. Intervent. 5(4): 214-222 (Abstract only), published 2003); and Ramakrishnan et al. (U.S. Pat. No. 7,060,271, issued 13 June 2006, cited by Applicant). The basis for this rejection is set forth at pp. 10-13 of the previous Office action (mailed 19 December 2024).
12. Claims 1, 62-69, 78-81, 85, 87-96, 98-101 remain rejected, and newly added claims 102-103 are rejected under 35 U.S.C. 103 as being unpatentable over Mabry et al. (mAbs 2(1):20-34, published 2010; cited by Applicant), and further in view of Wiegand et al. (U.S. Pat. No. 9,265,827; priority to 2013), Serruys et al. (Int. J. Cardiovasc. Intervent. 5(4): 214-222 (Abstract only), published 2003); Ramakrishnan et al. (U.S. Pat. No. 7,060,271, issued 13 June 2006, cited by Applicant); Ashman et al. (U.S. Pat. No. 8,680,245, issued 25 March 2014); Marquette et al. (WO2013/093809, published 27 June 2013; cited by Applicant); and Charles (WO 2007/100902, published 07 September 2007; cited by Applicant). The basis for this rejection is set forth at pp. 4-8 of the previous Office action (mailed 19 December 2024).
13. Mabry et al. teach fusion proteins comprising a single-chain antibody fragment that binds PDGFRB, a single chain antibody fragment that binds VEGF-A, fused to a linker, human Fc (See abstract).
14. Wiegand et al. teach antibodies which bind PDGFRB as well as VEGF traps (Aflibercept) comprising D2 from VEGFR-1 and D3 from VEGFR-2, which share 100% sequence identity with D2 of SEQ ID NO: 34 and D3 of SEQ ID NO: 35, respectively, of the instant application. It is noted that U.S. Pat. No. 7,087,411 (incorporated by reference by Wiegand et al. at column 23, lines 20-24) discloses that the components of the fusion protein (i.e., D2 of VEGFR1 and D3 of VEGFR2) may be connected directly to each other or be connected via a linker (See column 1, line 65 to column 2, line 3).
15. Serruys et al. disclose fab fragments which bind PDGFRB, and Ramakrishnan et al. disclose antibodies which bind PDGFRB, including antibody 2A1E2 having an IgG1 heavy chain and kappa light chain, as well as humanized and fab fragments thereof (See Column 5, lines 20-36, Column 9 line 33 to Column 10 line 11, Column 14, lines 32-67).
16. It would have been obvious at the time the invention was filed to modify the fusion proteins taught by Mabry et al and substitute the VEGF Trap as taught by Weigand et al for the single-chain antibody fragment which binds VEGF-A as disclosed in Mabry, as well as substitute the PDGFRB antibody taught by Wiegand et al., the fab fragment taught by Serruys et al. or the PDGFRB antibody 2A1E2 or fab fragment thereof taught by Ramakrishnan et al for the single-chain antibody fragment that binds PDGFRB as taught by Mabry. The motivation to do so is disclosed by Mabry et al, which discloses that targeting both the VEGF and PDGF pathways has the potential to increase the efficacy of anti-angiogenic therapy (See Mabry et al, abstract, for example), and Weigand et al who teaches combination therapy with an antibody which binds PDGFRB and a VEGF trap (See column 23). The expectation of success is high since fusion proteins comprising antibodies are well-known in the art. Furthermore, given that there are only 2 possible attachment points for the PDGF antibody and the VEGF receptor extracellular trap segment (either to the light chain or the heavy chain of the antibody), it would simply require routine experimentation to determine the optimal orientation of the fusion construct, either wherein the VEGF Trap is fused via the linker to the N-terminus of the PDGF antibody, or the VEGF Trap is fused via linker to the C-terminus of the PDGF antibody.
17. None of the references teach wherein the linker attaching the VEGF Trap to the PDGF antibody comprises the amino acid sequence of SEQ ID NO: 40 or SEQ ID NO: 41 (claims 80 and 88), or wherein the PDGF antibody has a heavy chain with a Q347C or an L443C mutation (claim 69), or wherein a phosphorylcholine-containing polymer is conjugated to the cysteine.
18. However, the use of said linkers, heavy chain mutants, and phosphorylcholine-containing polymers were all known in the art at the time the invention was filed, as evidenced by the Specification at pg. 14[0109] (linkers) and pg. 54[0271] (heavy chain mutations). Ashman et al. antibody-epitope-binding domain protein fusions, and disclose the use of linkers (including SEQ ID NO: 40 and SEQ ID NO: 41 of the instant claims (See columns 15-16) to link the two molecules. Marquette et al. discloses engineered antibody constant regions, including the substitutions Q347C and L443C in the IgG heavy chain, and teaches that the substitutions are useful for conjugation (See pg. 3, pg. 38, pg. 135, Table 13, Table 14, and pg. 161), including conjugation of a polymer to the antibody which are useful to achieve extended half-life (See pp. 119-120). Charles discloses phosphorylcholine-containing polymers, linear or branched, and having a molecular weight between 0.5kDa-800 kDa, including the instantly claimed HEMA-PC, which are useful for increasing the half-life of a biologically active agent, including antibodies, in a patient (See pg. 1; pg. 15[0023]-[0024]; pg. 16; pg. 20[0044]; pg. 20 [0046]).
19. It would have been obvious at the time the invention was filed to utilize the linkers taught by Ashman et al. to attach the VEGF Trap of Wiegand et al. to the PFGF antibody taught by either Wiegand et al. or Ramakrishnan et al, and to modify the PDGF antibody heavy chain with a Q347C or an L443C mutation as taught by Marquette et al. to conjugate a phosphorylcholine- containing polymer as taught by Charles. The motivation to do so is disclosed by Ashman et al, which discloses that the linkers are useful for linking antibodies to proteins (See columns 14-15), and Marquette et al. et al who teaches these cysteine substitutions in the heavy chain permits easier conjugation (See pg. 3, pg. 38, pg. 135, Table 13, Table 14, and pg. 161), including conjugation of a polymer to the antibody which are useful to achieve extended half-life (See pp. 119-120), and Charles discloses phosphorylcholine-containing polymers, including HEMA-PC that are useful for increasing the half-life of biologically active agents, including antibodies. The expectation of success is high since fusion proteins comprising utilizing both the linkers, the substitutions Q347C and L443C in the IgG heavy chain to promote conjugation of substances such as half-life extending polymers, and phosphorylcholine-containing polymers, including HEMA-PC, are known in the art. Thus, the claims 1, 62-69, 78-81, 85, 87-96, 98-103 are prima facie obvious over the combined teachings of the prior art.
Response to Arguments
20. Applicant’s arguments as they pertain to the rejections have been fully considered but are not persuasive for the following reasons.
21. Applicant argues at pp. 6-7 of the Response (filed 04 September 2025) that there is no reasonable expectation of success in combining in a fusion protein a VEGF antagonist with an anti-PDGF or anti-PDGFR antibody in the recited arrangement, citing Mabry that teaches “the manufacturability of these complex proteins at large scale continues to be a significant hurdle to the development of bsAbs [bispecific antibodies]”. Applicant argues that Mabry provides no guidance for modifying its bispecific fusion proteins based on scFvs and replacing one of the scFvs with another binding molecules, let alone a VEGF Trap, and in the absence of this guidance one of ordinary skill in the art would not have had a reasonable expectation of success in modifying Mabry’s bispecific fusion protein based on scFvs that have “superior stability”.
22. Applicant's arguments have been fully considered but are not found persuasive for the following reasons. Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In the instant case, the motivation to make a fusion comprising a VEGF Trap-PDGFR antibody fusion is disclosed by the combined teachings of Mabry et al, which discloses that targeting both the VEGF and PDGF pathways has the potential to increase the efficacy of anti-angiogenic therapy (See Mabry et al, abstract, for example), and Weigand et al who teaches combination therapy with an antibody which binds PDGFRB and a VEGF trap (See column 23), which binds VEGF-A with high affinity. The expectation of success is high since methods of making fusion proteins, including fusion proteins comprising antibodies, are well-known in the art, and given that only 2 orientations of the components of the fusion protein of a PDGF antibody and VEGF receptor extracellular trap segment are possible, it would simply require routine experimentation to determine the optimal orientation of the fusion construct. Similarly, given that there are only 2 possible attachment points for the PDGF antibody and the VEGF receptor extracellular trap segment (either to the light chain or the heavy chain of the antibody), it would simply require routine experimentation to determine the optimal orientation of the fusion construct. The courts have found patent may be found invalid as obvious if "there are a finite number of identified, predictable solutions, [and] a person of ordinary skill has good reason to pursue the known options within his or her technical grasp." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 127 S.Ct. 1727, 167 L.Ed.2d 705 (2007). See MPEP 2143(I)(E).
23. Applicant argues at pg. 8 of the response that the cited portions of Charles do not actually disclose that the polymer includes 2-30 arms, and the cited portions do not suggest modifying Charles’s polymer to arrive at a phosphorylcholine-containing polymer having the recited combination of features, including 9 arms. Moreover, Applicant argues the Examiner has not provided any reason why one of ordinary skill in the art would have modified Mabry’s fusion protein and looked to Charles to select a polymer having 9 arms, which Applicant has asserted that the cited portions of Charles has not disclosed.
24. Applicant's arguments have been fully considered but are not found persuasive for the following reasons. While the Examiner acknowledges that the cited portions of Charles do not specifically recite wherein the polymer has 9 arms, Charles does disclose phosphorylcholine-containing polymers, linear or branched, and having a molecular weight between 0.5kDa-800 kDa, including the instantly claimed HEMA-PC, which are useful for increasing the half-life of a biologically active agent, including antibodies, in a patient (See pg. 1; pg. 15[0023]-[0024]; pg. 16; pg. 20[0044]; pg. 20 [0046]), and phosphorylcholine-containing polymers, specifically HEMA-PC, having 9 arms are disclosed in the art as evidenced by Charles (WO 2013/059137; published 25 April 2013; cited by Applicant). The motivation to modify the Mabry’s fusion protein is disclosed by Charles, who teaches phosphorylcholine-containing polymers, including HEMA-PC, are useful for increasing the half-life of biologically active agents, including antibodies.
Summary
25. No claim is allowed.
Conclusion
26. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Advisory Information
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/J.L/Examiner, Art Unit 1647 December 13, 2025
/Christine J Saoud/Primary Examiner, Art Unit 1645