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 .
Status of Application, Amendments and/or Claims
The amendment and Applicant’s arguments, filed 09 February 2026, have been entered in full. Claims 18-38 are canceled. Claims 1 and 12 are amended. Claims 1-17, 39-44 are under examination.
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 09 February 2026) was received and comply with the provisions of 37 CFR §§1.97, 1.98 and MPEP § 609. It has been placed in the application file and the information referred to therein has been considered as to the merits.
Withdrawn Objections And/Or Rejections
The objection specification because of sequence deficiencies, as set forth at pages 2-5 of the previous Office Action (12 August 2025), is withdrawn in view of the amendment (09 February 2026).
The rejection to claims 12-14 and 40 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth at pages 5-6 of the previous Office Action (12 August 2025), is withdrawn in view of the amendment (09 February 2026).
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.
Claims 1-11, 15, 16, 39, 41-44 (and claims 12-14 and 40) remain rejected under 35 U.S.C. 103 as being unpatentable over Eveleth et al. (WO 2018/204847; published 08 November 2018) in view of Graham et al. (US 2021/0353714; published 18 November 2021; priority date 10 May 2018).
The basis for this rejection is set forth at pages 6-10 of the previous Office Action (12 August 2025). Newly amended claim 12 and dependent claims 13, 14 and 40 are added to the rejection.
APPLICANT’S ARGUMENTS: Applicant submits that the cited references fail to teach or suggest the pharmaceutical formulation recited in claim 1 and that the rejection relies on impermissible hindsight reconstruction. Applicant argues that there is a lack of motivation for one of ordinary skill in the art to modify Eveleth's formulation based on Graham's teaching to arrive at the claimed pharmaceutical formulation.
Applicant submits that Graham discloses histidine in the context of different formulation system, with a different combination of excipients and formulation objectives. Applicant argues that Graham teaches pharmaceutical formulations comprising high concentrations of VEGF receptor fusion protein. VEGF receptor fusion proteins are a large multidomain biologic, generally having much higher molecular weights than FGF-1. Applicant argues that FGF-1 is a small, single-domain growth factor polypeptide. Applicant argues that given these differences in the teachings of Graham and Eveleth with respect to preparation of formulation including VEGF receptor fusion protein, there is a lack of motivation for a person of ordinary skill in the art to combine their teachings to arrive at the claimed formulation.
Applicant argues that Graham does not teach or suggest incorporating histidine into the specific formulation of Eveleth or selecting the particular combination of components recited in the claim 1. Applicant argues that Graham discloses histidine as one option within a long list of alternative buffers and there is no teaching or suggestion in Graham to select histidine among other possible buffers. Applicant argues that Graham provides a long list of formulations with various components at a wide range of concentrations (Graham at paragraphs [0156]-[0246]). Applicant argues that in those formulations, histidine was included as one example among various available buffers. Graham's disclosure does not provide any specific teaching, guidance, or preference for selecting histidine as a component of the particular formulation recited in claim 1.
Applicant maintains that a person of ordinary skill in the art would lack any reasonable expectation of success that selecting histidine among a long list of possible buffers in combination with other ingredients with their respective concentrations would arrive at the claimed formulation. Applicant argues that to arrive at the claimed formulation recited in claim 1 based on Graham and Eveleth, a person of ordinary skill in the art would need to screen several buffer candidates, excipient combinations, and concentration ranges, and to conduct extensive experimentation to arrive at the claimed formulation.
Applicant discusses the instant specification, specifically Example 4 and paragraph 0414. Applicant argues that the claimed formulation demonstrates stability benefits which are unexpected and nonobvious to a person of ordinary skill in the art in light of the teachings of Graham and Eveleth, alone or in combination, nor would they have been reasonably expected based on general knowledge in the art.
Applicant’s arguments have been fully considered but are not found persuasive for the following reasons:
1. Eveleth et al. teach a pharmaceutical formulation comprising a modified FGF1 polypeptide that is 100% identical to instant SEQ ID NO:2, wherein said formulation comprises tonicity modifying agents and surfactant polysorbate 80. Eveleth et al. teach said formulation is suitable for ophthalmological formulations. Eveleth et al. teach delivery of said formulation to the eyes via eye drops, intraocular, and periocular administration.
The only elements Eveleth et al. do not teach regarding the ophthalmological formulation are the concentration of polysorbate 80; the concentration of the tonicity modifying agents and the use of histidine.
Graham et al. teach ophthalmic formulations comprising a vascular endothelial
growth factor (VEGF) receptor fusion protein (abstract).
Graham et al. teach buffers for use herein refer to solutions that resist pH change by use of acid-base conjugates. Graham et al. teach buffers are capable of maintaining pH in the range of from about 5.0 to about 6.8, and more typically, from about 5.8 to about 6.5, and most typically, from about 6.0 to about 6.5. In some cases, the pH of the formulation of the present invention is about 5.8. Graham et al. teach example buffers for inclusion in formulations herein include histidine-based buffers, for example, histidine, histidine hydrochloride, and histidine acetate. Graham et al. teach the buffer is from about 5 mM to about 25 mM. Graham et al. teach histidine at a concentration of 10 mM.
Graham et al. teach suitable surfactants herein have been shown to be non-ionic and include polysorbate 20, polysorbate 80 and mixtures thereof. Graham et al. teach surfactants in the formulations can be present at from about 0.02% to about 0.1% weight per volume (w/v), and more typically, about 0.02% to about 0.04% (w/v). In some cases, the surfactant is about 0.1% (w/v).
Graham et al. teach thermal stabilizers for use herein refers to ingredients that
provide thermal stability against thermal denaturation as well as protect against loss of
VEGF receptor fusion protein potency or activity. Graham et al. teach suitable thermal
stabilizers can be sucrose, trehalose, sorbitol or mannitol. Graham et al. teach that sorbitol can be present at between about 4% (w/v) and 9% (w/v) (e.g., about 5%).
Contrary to the presented arguments, a person of ordinary skill in the art would have a reasonable expectation of success for selecting histidine in combination with the other ingredients with their respective concentrations to arrive at the claimed formulation.
Additionally, a pharmaceutical formulation comprising a modified fibroblast growth factor 1 (FGF-1) polypeptide that is 100% identical to instant SEQ ID NO:2, surfactant polysorbate 80 and tonicity modifying agents, as taught by Eveleth et al., wherein the surfactant is in a concentration of about 0.01% (w/v) to about 10% (w/v), the tonicity modifying agent is at a concentration of about 1% (w/v) to about 10% (w/v) and histidine is at a concentration of about 0.1 mM to about 20 mM, as taught by Graham et al., would have the functional properties, as recited in claims 12, 13, 14 and 40.
2. Applicant’s arguments regarding the concentration of VEGFR receptor fusion protein and its molecular weight compared to FGF-1, and the lack of motivation for a person of ordinary skill in the art to combine their teachings to arrive at the claimed formulation are not found persuasive.
Graham et al. teach the use of histidine buffers to maintain a particular pH of the formulation. It is unclear how pH would be affected by the concentration or molecular weight of a protein and Applicant has not submitted references that teach this, in particular that of VEGF receptor fusion protein compared to FGF-1.
3. Applicant’s argument that Graham provides a long list of formulations with various components at a wide range of concentrations (Graham at paragraphs [0156]-[0246]) and that histidine was included as one example among various available buffers, is not found persuasive.
Graham et al. only teaches 3 types of buffers; histidine based, citrate based or phosphate based. In addition, MPEP 2123 states that disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or non-preferred embodiments (In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
4. Applicant’s argument that a person of ordinary skill in the art would lack any reasonable expectation of success selecting histidine among a long list of possible buffers in combination with other ingredients with their respective concentrations to arrive at the claimed formulation, is not found persuasive.
One skilled in the art is choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense (see MPEP 2145). MPEP 2144.05 teaches: "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”).
5. Applicant arguments regarding the claimed formulation stability benefits and unexpected and nonobvious results are not found persuasive because Applicant is discussing a pharmaceutical formulation that is not within the scope of the claims, as currently recited.
That is to say, the formulation discussed by Applicant recites a SEQ ID NO: for the modified FGF-1 polypeptide, a specific concentration of histidine, a specific concentration of polysorbate 80, a specific concentration of sorbitol and a specific pH.
The scientific reason and evidence as a whole indicates that the rejection should be maintained.
Claim 17 remains rejected under 35 U.S.C. 103 as being unpatentable over Eveleth et al. (WO 2018/204847; published 08 November 2018) in view of Graham et al. (US 2021/0353714; published 18 November 2021; priority date 10 May 2018), as applied to claim 1 above, and further in view of Jonker et al. (US 2013/0116171; published 09 May 2013).
The basis for this rejection is set forth at pages 10-12 of the previous Office Action (12 August 2025).
APPLICANT’S ARGUMENTS: Applicant argues that claim 17 depends from claim 1 and includes all of the elements of claim 1. Applicant argues that as stated above, claim 1 is nonobvious over Graham and Eveleth, alone or in combination, and Jonker does not cure the deficiency of Graham and Eveleth.
Applicant argues that for at least the same reasons stated above, claim 1 is nonobvious over Eveleth, Graham, and Jonker, alone or in combination, and claim 17 is also nonobvious over Eveleth, Graham, and Jonker, alone or in combination due to at least its dependency upon claim 1.
Applicant’s arguments have been fully considered but are not found persuasive for the reasons stated above regarding the rejection to claims 1-16, 39-44 under 35 U.S.C. 103 as being unpatentable over Eveleth et al. (WO 2018/204847; published 08 November 2018) in view of Graham et al. and for reasons of record.
The scientific reason and evidence as a whole indicates that the rejection should be maintained.
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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/R.M.D/Examiner, Art Unit 1647
3/23/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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