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 .
Applicant’s response filed on 12/08/2025 is acknowledged and fully considered.
Status of Application, Amendments, And/Or Claims
The amendments of claims 1, 8, 11-12, 22 and 35, and the cancellation of claims 3-7, 9-10, 13-21, 23-25, and 29-34 have been made of record.
Claims 1-2, 8,11-12, 22, 26-28 and 35-44 are pending and under consideration.
Response to Arguments
Claim Rejections - 35 USC § 102-withdrawn
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.
The rejection of claim(s) 1-2 under 35 U.S.C. 102(a)(1) as being anticipated by CN 101693016A (pub. Date 4/4/14/2010) is withdrawn in view of applicant’s amendments of claim 1 to incorporate the limitation of non-rejected claims.
The rejection of claim(s) 1-2, 8,11-12, 22, 26-28, 35, 41-42 and 44 under 35 U.S.C. 102(a)(1) as being anticipated by Park et al (IDS, US Pub. No. 20160376342, US Pat. No. 9,982,032) is withdrawn in view of applicant’s amendments to claim 1. However, upon further consideration necessitated by claim amendments a new ground of rejection is made under 35 USC 103 set forth below.
The rejection of claim(s) 1-43 under 35 U.S.C. 102(a)(1) as being anticipated by Furfine et al (IDS, US Pub. No. 20160213608, US Pat. No. 9914763) is withdrawn in view of applicant’s amendments to claim 1. However, However, upon further consideration necessitated by claim amendments a new ground of rejection is made under 35 USC 103 set forth below.
New Ground of rejection necessitated by Applicant’s amendments
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 8 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.
Regarding claim 8, the phrase "wherein the recombinant fusion protein further comprises aflibercept" renders the claim indefinite because the art discloses aflibercept as a fusion protein comprising VEGFR-1 domain 2, VEGFR-2 domain-3 and IgG Fc. The formulation of claim 1 could comprise aflibercept. Therefore, it is not clear how the fusion protein of claim 1 can further comprise another fusion protein (i.e., aflibercept). The metes and bounds of the claim cannot be determined. See MPEP § 2173.05(d).
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.
Claim(s) 1-2, 8, 11-12,22, 26-28 and 35-44 is/are rejected under 35 U.S.C. 103 as being unpatentable over Park et al (IDS, US Pub. No. 20160376342, US Pat. No. 9,982,032) in view of Furfine et al (IDS, US Pub. No. 20160213608, US Pat. No. 9914763).
It is noted to applicants that the composition of the instant claims do not require that the composition of claim 1 be stable at 40+ °C and 75% relative humidity after 4 weeks as argued in their Rem. of 12/8/2025.
The instantly claimed invention is broadly drawn to a stable pharmaceutical formulation comprising: 5 to 100 mg/ml of a recombinant fusion protein comprising: a vascular endothelial growth factor (VEGF) receptor extracellular domain 1 component comprising amino acids 27 to 129 of SEQ ID NO: 2;a VEGF receptor extracellular domain 2 component comprising amino acids 130 to 231 of SEQ ID NO: 2: and an Fc region component comprising amino acids 232 to 457 of SEQ ID NO:2 (known in the art as aflibercept); 0.01 to 0.1% (w/v) of polysorbate; 1 to 20% (w/v) of trehalose; 1 to 20 mM of histidine; and 30 mM or less of sodium chloride, wherein the stable pharmaceutical formulation is free of phosphoric acid (claim 1), wherein in the stable formulation is in a liquid form (claim 2). The formulation of claim 1, wherein the recombinant protein further comprises aflibercept (claim 8). The stable composition of claim 1, wherein the polysorbate comprises polysorbate 20 (claims 11-12). The stable pharmaceutical formulation of claim 1, wherein the stable pharmaceutical formulation has a pH of 5.0 to 7.0 (claim 26). The stable pharmaceutical formulation of claim 1, wherein the stable pharmaceutical formulation is free of NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4, or a mixture thereof (claim 27). The stable pharmaceutical formulation of claim 1, wherein the stable pharmaceutical formulation is free of a chelating agent (claim 28), wherein the formulation is stable at 5 °C for 10 days or 9 months (claims 36-40),The stable formulation of claim 1, wherein the formulation is for intraocular administration (claim 41), wherein the formulation does not require reconstitution step (42), wherein the formulation is in a glass vial (claims 43), and wherein the stable formulation is in a pre-filled syringe (claim 44).
Park et al teach a stable liquid pharmaceutical composition comprising a VEFG receptor fusion protein with a human immunoglobulin (IgG) (abstract). They teach that the fusion protein comprises aflibercept (abstract). They teach that the fusion protein comprises external domain of VEGF receptor which is fused with human IgG Fc (see paragraph [0017]). They teach that the fusion protein is from 10-40 mg/ml [0018]. Regarding claim 26, Park et al teach VEGF receptor fusion composition comprising buffer that includes histidine salt having pH 5.7 to 6.2, a stabilizer that includes sugars and surfactant, wherein in histidine salt is 10 mM to 50 mM histidine-HCl; sugar is any one including sucrose, trehalose, mannitol in about 2.5%-10%; and surfactant is any one including polysorbate 20, polysorbate 80 in about 0.01-0.03% (see paragraph [0070]). They teach an extracellular domain of a VEGF receptor and an Fc domain of human IgG are fused (see paragraph [0016]). Regarding claim 8, Park et al teach the fusion protein comprises aflibercept (see paragraph[0007] and claim 13). Regarding claims, 35-40, Park et al teach that the composition is stable at 5°C but see some aggregation at 50 °C temperature (Examples 1-5). They teach that the pharmaceutical composition can be prefilled syringe suitable for intravitreal administration [0010]. Park et al. do not teach to include NaF, Kbr, NaBr or others of claim 27 or a chelating agent as recited in claim 28. Park et al do not teach that the fusion protein comprises a VEGF receptor extracellular domain 1 comprising amino acids 27-129 of SEQ ID NO: 2; a VEGF receptor extracellular domain 2 component comprising amino acids 130-231 of SEQ ID NO: 2; and an Fc region comprising amino acids 232-457 of SEQ ID NO:2.
Furfine et al. teach a stable liquid pharmaceutical composition comprising a VEFG receptor fusion protein with a human immunoglobulin (IgG) comprising amino acid sequence set forth in SEQ ID NO: 4, which comprises the amino acid sequence of 100% sequence identity as being instantly claimed in claim 7 (see Search result in PE2E (Result number 24 from 97 duplicates, dated 8/28/2025 (US Pat. No. 7,608,261)). They teach that the ophthalmic formulation is provided in a pre-filled syringe or vial suitable for intravitreal administration [0039]. Regarding claims 36-40, Furfine et al. teach making an ophthalmic formulation stored in a glass vial at 5 °C with 0 to 0.1 turbidity at 3 months, 6 months, 9 months, 12 months, 18 months and 24 months (see Example 1 , Table 1, [0060]). They teach that the composition comprises 20 mM NaCl and the pH of the composition is 6.2-6.3 [0031-0032].
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use a fusion protein comprising a VEGF receptor extracellular domain 1 comprising amino acids 27-129 of SEQ ID NO: 2; a VEGF receptor extracellular domain 2 component comprising amino acids 130-231 of SEQ ID NO: 2; and an Fc region comprising amino acids 232-457 of SEQ ID NO:2 as taught by Furfine et al wherein the composition included NaCl at 20 mM having buffer pH of about 6.2 and to include in the buffer that comprises 10 mM to 50 mM histidine-HCl; sugar is any one including sucrose, trehalose, mannitol in about 2.5%-10%; and surfactant is any one including polysorbate 20, polysorbate 80 in about 0.01-0.03% as taught by Park et al. Additionally, one would have been motivated to do so because Furfine et al teach a VEGF receptor fusion protein with an Fc of SEQ ID NO: 4 that comprises the instantly claimed fusion protein comprising a VEGF receptor extracellular domain 1 comprising amino acids 27-129 of SEQ ID NO: 2; a VEGF receptor extracellular domain 2 component comprising amino acids 130-231 of SEQ ID NO: 2; and an Fc region comprising amino acids 232-457 of SEQ ID NO:2. Further, one would have a reasonable expectation of success in using a VEGF receptor fusion protein as taught by Furfine et al which comprises a VEGF receptor extracellular domain 1 comprising amino acids 27-129 of SEQ ID NO: 2; a VEGF receptor extracellular domain 2 component comprising amino acids 130-231 of SEQ ID NO: 2; and an Fc region comprising amino acids 232-457 of SEQ ID NO:2. Therefore, the instantly claimed invention would have been obvious to one ordinary skill in the art over the combined teaching in the prior art.
One would have had a reasonable expectation, barring evidence to the contrary, the composition would provide a product that has enhanced stability at 5 °C. Since the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. See the recent Board decision Ex parte Smith,--USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/GYAN CHANDRA/Primary Examiner, Art Unit 1674