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 .
Detailed Action
Claims 3, 7-13, 15-22, 24-29, 31-34, 45-51 are pending in the instant application.
Election/Restrictions
Applicant elected without traverse Group 1 (claims 3, 7-13, 15-22, 24-29, 31-34) drawn to a composition and without traverse SEQ ID NO:12 wherein one or more histidines were oxidized to 2-oxo-histidine in the response filed March 18, 2026. Applicants additionally elected or more asparagines of the VEGF mini trap are N-glycosylated in the response to a further restriction requirement July 16, 2026.
The restriction is deemed proper and is made FINAL in this office action.
Claims 11, 45-51 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention/species, there being no allowable generic or linking claim.
Claims 3, 7-10, 12-13, 15-22, 24-29, 31-34 are examined on the merits of this office action.
Claim Objection
Claims 24-27, 29 are all objected to for the following informality: Claims 24-27 and 29 are objected to under 37 C.F.R. 1.75/MPEP608.01(m) as being improperly formatted, in that the claim utilizes bulletin points or structural symbols. Patent claims must consist of a continuous sentence utilizing proper paragraph indentation and alphanumeric sub parts rather than graphic symbols.
Claim 13 is objected to: the semicolon following “BY2 and BY4 in last line should be removed.
Claim 15 is objected to: the limitation “comprises” should be replaced with -comprising-.
Sequence Compliance
This application fails to comply with the requirements of 37 C.F.R 1.821-1.825 for the reasons set forth on the attached Notice to Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/or Amino Acid Sequence Disclosures. Applicant must comply with the requirements of the sequence rules (37 CFR 1.821-1.825) before the application can be examined under 35 U.S.C 131 and 132. Each sequence disclosed must appear separately in the “Sequence Listing.” Each sequence set forth in the “Sequence Listing” must be assigned a separate sequence identifier. Applicant failed to include sequence identifiers in either Figure 1 or in the description of Figures 1-2, 14B.
Drawings
The drawings are objected to because according to 37 CFR 1.821(b) the sequence information so conveyed must still be included in a "Sequence Listing” and the sequence identifier (“SEQ ID NO:X”) must be used, either in the drawing or in the “Brief Description” of the Drawings. Figures 1-2, 14B comprises sequences without sequence identifiers. There are no sequence identifiers listed in Figures 1-2, 14B or the description of Figures 1-2, 14B. 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.
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 7, 9-10, 19, 25-27, 34 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 7, claim 7 depends from claim 3 and requires one or more asparagine residues be glycosylated and/or one or more tryptophan residues be dioxidized. Claim 3 however, claims a VEGF mini trap consisting of the amino acid sequence of SEQ ID NO:12 wherein one or more histidines of said VEGF mini trap are oxidized to 2-oxo histidine. The transitional phrase “consisting of” is closed and excludes amino acid residues or other structural components not encompassed by the recited peptide, except to the extent provided by the claim. Glycosylated asparagine and deoxidized tryptophan are chemically and structurally different from the corresponding unmodified asparagine and tryptophan residues of SEQ ID NO:12. It is therefore unclear how the peptide can simultaneously consist of SEQ ID NO:12 and contain the additionally modified residues required by claim 7. Accordingly, the metes and bounds of claim 7 are unclear.
Claim 9 depends from claim 3 and recites limitations involving carboxmethylated cysteine and 2-oxo-histidines in the recited oligopeptide/digestion products. Carboxmethylated cysteine is structurally different from the cysteine residue specified by SEQ ID NO:12. The language of claim 9 does not clearly establish whether the carboxylated cysteines are modifications present int eh VEGF mini trap itself or are generated during preparation of the recited digestion products. It is therefore unclear whether the subject matter of claim 9 remains within the peptide consisting of SEQ ID NO:12 required by claim 3.
Regarding claim 10, Claim 10 depends from claim 3 and recites limitations involving carboxmethylated cysteine and 2-oxo-histidines in the recited oligopeptide/digestion products. Carboxmethylated cysteine is structurally different from the cysteine residue specified by SEQ ID NO:12. The language of claim 10 does not clearly establish whether the carboxylated cysteines are modifications present int eh VEGF mini trap itself or are generated during preparation of the recited digestion products. It is therefore unclear whether the subject matter of claim10 remains within the peptide consisting of SEQ ID NO:12 required by claim 3.
Claim 19 recites the limitation "the aqueous buffer" in the last line. There is insufficient antecedent basis for this limitation in the claim. Furthermore, the recitation of “the VEGF mini trap is in a loading buffer before application to the resin which is the equilibration buffer” renders it unclear whether “which is the equilibration buffer” modifies the loading buffer or the resin.
Regarding claim 25, Claim 25 depends from claim 3 and requires one or more additional chemical modifications including N-glycosylated asparagine, O-glycosylated serine or threonine, deamidated Asn, conversion of Asp-Gly, oxidized methionine, conversion of tryptophan to N-formylkynurenine, and/or conversion of arginine to Arg-3-deoxyglucosone. These chemically modified residues are structurally different from the corresponding unmodified amino acid residues of SEQ ID NO:12, just as N-formylkynurenine is chemically distinct from tryptophan. It is therefore unclear how the claimed minitrap can contain such chemically altered residues while simultaneously consisting of SEQ ID NO:12 required by claim 3.
Regarding claim 26, claim 26 depends on claim 3 and requires glycosylation of the VEGF mini trap. A glycosylated amino acid sequence/Asn residue is chemically and structurally different from the corresponding unmodified residues specified by SEQ ID NO:12. It is therefore unclear how the VEGF mini trap can both consist of SEQ ID NO:12 as required by claim 3 and comprise (which is an open transitional phrase) glycosylation as required by claim 26.
Regarding claim 27, claim 27 depends on claim 3 and requires glycosylation of specified asparagine residues, including Asn123, Asn196, with particular glycan species and percentages. A glycosylated asparagine residue is chemically and structurally different from the corresponding unmodified asparagines residue specified by SEQ ID NO:12. It is therefore unclear how the VEGF mini trap can both consist of SEQ ID NO:12 as required by claim 3 and comprise covalently glycosylated asparagine residue required by claim 27.
Claim 27 is further indefinite because it recites percentages of plural “asparagine 123 residues” and “asparagine 196 residues” while referring to singular “the VEGF mini trap”. A single VEGF mini trap contains a discrete residue at each specified sequence position and therefore cannot itself have, for example, a stated percentage of plural Asn123 residues bearing a particular glycan. The claim does not clearly identify whether the percentages refer to a population of VEGF mini trap molecules, a population of glycopeptides or another population and consequently does not clearly establish the denominator for the recited percentages.
Claim 34 is rejected as being indefinite because the limitation “in association with a further therapeutic agent” fails to define with reasonable certainty the required relationship between the composition of claim 2 and the further therapeutic agent. The term “associated with” is vague and is defined as connected to. It is suggested that Applicants amend the claim to recite “in combination with”.
Claim Rejections - 35 USC § 112
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.
Claims 7, 8-10,13, 25-27 are 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.
Claim 7 depends from claim 3, which requires the VEGF mini trap to consist of the amino acid sequence of SEQ ID NO:12, but further requires one or more asparagines to be glycosylated and/or one more tryptophans to be dioxidized. Such modified residues are structurally different from the corresponding amino acid residues of SEQ ID NO:12 and therefore do not further limit the subject matter required by claim 3.
Claim 8 claims “between 0.1% to 2% of histidines” are oxidized to 2-oxo-histidine, but fails to specify the population or denominator from which the percentage is being calculated. There are only 8 histidine residues in the VEGF mini trap described in claim 3 and thus, 1 histidine would be 12.5%. Thus, it is not plausible that 0.1% of the histidines in the VEGF mini trap claimed in claim 3 could be oxidized. . It is therefore unclear whether the percentage refers to the histidine residues within an individual VEGF mini trap or a population of the VEGF mini trap (the composition), such that the metes and bounds of the claim cannot be determined.
Claim 9 depends from claim 3 but recites carboxymethylated cysteine residues Carboxymethylated cysteine is structurally different from the cysteine residue specified by SEQ ID NO:12. Claim 3 expressly permits conversion of histidine to 2-oxo-histidine but does not provide for conversion of cysteine to carboxymethylated cysteine. Accordingly, to the extent claim 9 requires carboxymethylated cysteine in the claimed mini trap, it does not further limit the subject matter of claim 3.
Claim 10 depends from claim 3 but requires chemically modified amino acid residue(s) no provided for by the closed “consisting of” sequence limitation of claim 3. Because such modified residue(s) are structurally different from the corresponding residues of SEQ ID NO:12, claim 10 does not further limit the subject matter of claim 3 as required by 112(d).
Claim 13 is dependent on claim 3 and claim 3 claims that the composition is no more brown yellow than European Color Standard BY2. Claim 13 depends 3 and claims alternatives including BY3-7, between BY2 and BY3 or between BY2 and BY4 which do not further limit and broaden the scope of claim 3.
Claim 25 depends from claim 3 but requires additional chemical modifications, including glycosylated asparagine, O-glycosylated serine or threonine, deamidated asparagine, modified Asp-Gly motifs, oxidized methionine, conversion of tryptophan to N-formylkynurenine, and/or conversion of arginine to Arg-3-deoxyglucosone. These modified residues are structurally different from the corresponding residues of SEQ ID NO:12. Thus, claim 25 requires subject matter outside, rather than further limiting the closed sequence of claim 3.
Claim 26 depends from claim 3 and requires one or more asparagines to bear specified glycosylations. Such glycosylated asparagine residues are structurally different from the corresponding asparagine residues of SEQ ID NO:12. Claim 26 therefore does not further limit the subject matter of claim 3 but requires chemically modified subject matter outside its closed sequence limitation.
Claim 27 depends from claim 3 and requires specific Man5, Man6-phosphate, Man7 and/or high mannose glycosylation at particular asparagine residues. The resulting glycosylated asparagine residues are structurally different from the corresponding asparagine resides of SEQ ID NO:12. Accordingly, claim 27 requires subject matter outside, rather than a further limitation of, the peptide consisting of SEQ ID NO:12 required by claim 3.
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
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 3, 7, 9-10, 12, 15-22, 24-26, 29, 31-32, 34 are rejected under 35 U.S.C. 103 as being unpatentable over Daly (US20060058234 A1) in view of Danos (WO2019079494) in view of Kabakoff (WO2019148020 A1) and Bridgewater (J Am Soc Mass Spectrom 2007, 18, 553–562).
Daly teaches a method of administering VEGF Traps for treating VEGF associated diseases (see abstract, claims 16, 19-21). Daly teaches administering VEGF mini traps (see paragraphs 0009, 0043). Daly teaches “the mini-traps of the invention, a smaller VEGF trap was generated by directed cleavage of a dimerized VEGF trap having a cleavage region (C-region) generated in a Fc domain (Example 2). The truncated trap exhibited comparable affinity for VEGF and half-life as the full-sized parent trap” (see paragraph 0063). Daly additionally teaches wherein the formulations are aqueous (see paragraph 0053-0054).
Daly is silent to wherein one or more histidines are oxidized and the specific truncated sequence of a peptide consisting of SEQ ID NO:12.
However, Danos teaches VEGF receptor fusion proteins and VEGF mini-traps comprising VEGFR1 Ig domain 2 and VEGFR2 Ig domain 3 together with a truncated multimerizing/Fc component (see abstract, Figure 4). The reference further teaches Fc less/truncated VEGF-Trap constructs and removal of C terminal residues, including lysine or glycine-lysine, and recognizes that VEGF Trap proteins undergo posttranslational modifications (see Figure 4). Figure expressly teaches an “Aflibercept. Fc(-)” construct. It identifies Flt-1 positions 1-102 and KDR positions 103-205, followed by hinge derived residues. The sequence of Figure shows alternatives at the c-terminal region, including “+/-PELLGG”. Thus, the reference teaches that the C-terminal residues following the VEGFR1/VEGFR2 receptor domains may be truncated or removed. It would have been obvious to select the claimed terminal form from the taught Fc(-) aflibercept variants because the references specifically teaches truncation and optional residues in the same c-terminal region, with the predictable result of producing the Fc-truncated VEGF binding protein while retaining the receptor domains.
The sequence of Danos differs from the instant claims by one amino acid (an extra Glycine residue) and one or more 2-oxo-histidine residues.
Kabakoff teaches of fusion proteins of IL-22 and FC (see abstract). Kabakoff teaches that “In some aspects of the disclosure, the substitutions, insertions, or deletions occur in regions outside of IL-22 (ie, in the Fc). In some aspects of the invention, the substitutions, insertions or deletions can be in the linker, hinge, CH2 domain, CH3 domain of the Fc fusion protein of IL-22. In certain particular aspects of the invention, the C-terminal Lys residue of Fc is deleted. In some other aspects of the invention, the C-terminal Gly and Lys residues of Fc are deleted” (see page 49, last line).
Danos teaches that “Oxidation, such as methionine, tryptophan, and histidine oxidation, is also associated with protein production and storage, and is caused by stressed cell culture conditions, metal and air contact, and impurities in buffers and excipients. The proteins expressed from transgenes in vivo may also oxidize in a stressed condition” (see paragraph 0057).
Bridgewater teaches (at page 553) oxidization of histidine residues in peptides to 2-oxo-histidine. Bridgewater further teaches at page 555 that oxidation involves the net addition of one oxygen atom to the histidine side chain and attributes the resulting effects to 2-oxo-histidine (see page 561).
It would have been before the effective filing date of the claimed invention to one of ordinary skill in the art to modify the VEGF mini trap of Daily according to the Fc(-) aflibercept/VEGF mini trap teachings of Danos to provide the claimed truncated VEGF fusion protein. On of ordinary skill in the art would have been motivated to do so because both references teach VEGF mini traps comprising VEGFR1 and VEGFR2 receptor domains and teach truncation removal of the Fc or C terminal region while retaining the VEGF binding. There would have been a reasonable expectation of success because Daily expressly reports that the truncated mini trap exhibited VEFG affinity comparable to the full sized parent trap and Danos teaches Fc(-) constructs retaining the VEGF receptor domains. This modification represents the use of a known technique to improve or modify a similar product in the same way and the selection of a known alternative from a finite number of identified, predictable solutions yielding predictable results.
Furthermore, it would have been obvious before the effective filing date of the claimed invention to one of ordinary skill in the art to further modify the Fc(-) VEGF trap of Danos by deleting the additional C-terminal glycine residue as taught by Kabakoff. One of ordinary skill in the art would have been motivated to do so because Danos teaches alternative truncations in the c-terminal region, while Kabakoff teaches deletion of the C-terminal residues, including a glycine and lysine, from Fc fusion proteins. There would have been a reasonable expectation of success because deletion of such terminal residues was expressly taught for Fc fusion proteins and would predictably provide the corresponding truncated protein without altering the VEGF receptor domains. This modification constitutes the application of a known technique to a similar product for the same purpose and the predictable variation of a known protein construct (see KSR rationales, MPEP 2143).
Regarding oxidative modification to one or more histidines, it would have been obvious before the effective filing date of the claimed invention to one of ordinary skill in the art for one or more histidine residues of the VEGF mini trap of Daily/Danos would comprise oxidized histidine species under the disclose production, storage and or in vivo conditions (in the pathological conditions of the eye/conditions to be treated). One of ordinary skill in the art would have been motivated to recognize such oxidized species because Danos teaches that histidine oxidation is associated with protein production and storage including under stressed conditions and air contact, and further teaches that proteins expressed in vivo may oxidize under stressed conditions (see paragraph 0057). Bridgewater teaches that histidine is susceptible to oxidation and that oxidation of histidine results in 2-oxo-histidine (see page 553). Thus, upon oxidation of the histidine containing VEGF mini trap taught by Daily/Danos, formation of 2-oxo-histidine would have been an expected consequence of the known oxidation processes (with storage and in vivo environment). The claimed 2-oxo-histidine species therefore represents the predictable result of subjecting the known histidine containing protein to the oxidative conditions taught in the prior art.
Regarding claims 7 and 25, Danos teaches N-linked Asn glycosylation (see figure 4).
Regarding claims 9-10, for the purpose of prior art examination, claim 9 is interpreted as requiring the VEGF mini trap of claim 3, notwithstanding the indefinite issues described in the above rejection. Accordingly, claims 9-10 is rejected for the same reasons as set forth with respect to claim 3. Furthermore, the combined references teach the same VEGF mini trap as claimed in claim 3 and thus, any proteolytic digestion (via Lys C and Trpsin) would predictably produce peptide fragments corresponding to the cleavage sites of the known sequence.
Regarding claim 12, Bridgewater teaches oxidation of histidine to 2-oxo-histidine (page 553) and thus meets the limitations of claim 12.
With respect to the limitation of the composition is no more brown yellow than European color standard BY2 (in claim 3), the combined prior art composition would inherently possess the claimed color because it comprises the same Aqueous VEGF mini trap composition in water.
Regarding claim 15, the limitations directed to expression of aflibercept, proteolytic cleavage thereof, and removal of the Fc domain are product by process limitations. Although claim 15 does not expressly require that VEGF mini trap itself to consist of SEQ ID NO:12, it requires production of the mini-trap by cleavage of aflibercept comprising SEQ ID NO:12 and presence of one or more 2-oxo-histidines. The combined prior art teaches the same or substantially the same Fc truncated VEGF binding product obtained from aflibercept with one or more 2-oxo-histidines. Absent evidence that the recited production process imparts a structural or functional distinction to the resulting mini trap, the process by which the product is produced does not distinguish the claimed production from the prior art.
With respect to claims 15-22 and 24, the recited process limitations are product by process limitations and patentability is determined based on the product itself rather than the process by which the product is made (see MPEP 2113). The prior art teaches the same VEGF mini trap product. Accordingly, where the claimed and prior art products are identical, the claimed product is presumed to possess the same structure and composition characteristics, notwithstanding differences in the recited method of manufacture. The Applicants has not established that expression in chemically defined medium, proteolytic cleavage, protein A purification, anion exchange chromatography, pH adjustment, filtration/diafiltration, viral inactivation or hydrophobic interaction chromatography imparts a structural or functional distinction in the resulting VEGF mini trap. Daly does teach “In order to further purify the factors, conventional ion exchange chromatography, hydrophobic interaction chromatography, reverse phase chromatography or gel filtration may be used” (see paragraph 0028) and also direct cleavage to generate smaller VEGF traps (see paragraph 0063).
Regarding claim 26, both Daly and Danos teaches N-linked glycosylation (see figure 4 Danos, see paragraph 0084, in particular Man-5 in Daly, also figure 1). Nevertheless, it would have been obvious that expression of the glycoprotein in a glycosylating host (such as CHO cells, paragraph 0043) would produce a population comprising N-linked glycoforms, including the recited glycan species in instant claim 26.
Regarding claim 29, Daly teaches expression in a CHO cell (see Example 5).
Regarding claim 31-32, Daly teaches pharmaceutical formulations (see paragraph 0017) and injection which would require an injection device (see paragraphs 0051-0052.
Regarding claim 34, Daly teaches administration with a further therapeutic agent (see paragraph 0045).
Claims 28 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Daly (US20060058234 A1) in view of Danos (WO2019079494) in view of Kabakoff (WO2019148020 A1) and Bridgewater (J Am Soc Mass Spectrom 2007, 18, 553–562) as applied to claims Claims 3, 7, 9-10, 12, 15-22, 24-26, 29, 31-32, 34 above, in further view of Graham (US20190343918).
The combined references of Daly, Danos, Kabakoff and Bridgewater are silent to the concentration of the VEGF mini trap and use in a prefilled syringe (injection device)
However, Graham teaches of aqueous formulations comprising VEGF mini trap proteins for injection (see claim 1, paragraphs 0009-0010, paragraph 0091) for treatment of ocular conditions (see abstract). Graham teaches concentrations of at least 80 mg/ml up to 120 mg/ml (see paragraph 0102, see also paragraphs 0242-0246). Graham teaches use in a pre-filled syringe.
It would have been obvious before the effective filing date of the claimed invention to formulate the VEGF mini trap of the combined references at the concentrations taught by Graham because Graham teaches such concentrations for aqueous injectable VEGF mini trap formulations (for the same therapeutic use). One of ordinary skill would have had reasonable expectation of successfully obtaining the concentrated aqueous VEGF mini trap formulation because Graham teaches such formulations for the same intended use. Furthermore, the concentration of the mini trap is a result effective variable and it would have been obvious to optimize the amount toa achieve optimal therapeutic effectiveness.
Regarding claim 33, it would have been obvious to provide the mini trap composition of the combined references in Grahams prefilled syringe because Graham teaches that prefilled syringe as a suitable delivery device for such injectable VEGF formulations (for the same intended purpose), with a reasonable expectation of successfully administering the formulation.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 15-22, 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 11180540. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 15 claims an aqueous composition comprising a VEGF mini trap with the Fc domain removed (see claim 15); and one or more oxidized histidines resulting in 2-oxo histidine (see claim 15).
Claims 15-22, 24 claim product by process steps. The recited process limitations are product by process limitations and patentability is determined based on the product itself rather than the process by which the product is made (see MPEP 2113). The prior art teaches the same VEGF mini trap product. Accordingly, where the claimed and prior art products are identical, the claimed product is presumed to possess the same structure and composition characteristics, notwithstanding differences in the recited method of manufacture.
US Patent No. 11180540 claims A method of producing afliberept MiniTrap (see claim 1); wherein aflibercept is cleaved to remove the Fc domain (see claim 1(b). US Patent No. 11180540 further claims wherein histidines are oxidized (see claims 4-5) and specifically 2-oxo-histidine (see claim 8 Sequences).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 15-22, 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11407813 in view of Bridgewater (see above reference). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 15 claims an aqueous composition comprising a VEGF mini trap with the Fc domain removed (see claim 15); and one or more oxidized histidines resulting in 2-oxo histidine (see claim 15).
Claims 15-22, 24 claim product by process steps. The recited process limitations are product by process limitations and patentability is determined based on the product itself rather than the process by which the product is made (see MPEP 2113). The prior art teaches the same VEGF mini trap product. Accordingly, where the claimed and prior art products are identical, the claimed product is presumed to possess the same structure and composition characteristics, notwithstanding differences in the recited method of manufacture.
US Patent No.11407813 claims a VEGF minitrap (see claim 1); wherein aflibercept was subject to proteolytic cleavage to remove the Fc domain (claim 1). US Patent No. 11407813 is silent to one or more 2-oxo-histidines (oxidative modification to histidine). However, Bridgewater teaches (at page 553) oxidization of histidine residues in peptides to 2-oxo-histidine. Bridgewater further teaches at page 555 that oxidation involves the net addition of one oxygen atom to the histidine side chain and attributes the resulting effects to 2-oxo-histidine (see page 561).
It would have been obvious before the effective filing date of the claimed invention to one of ordinary skill in the art for one or more histidine residues of the VEGF mini trap of US Patent No. ‘813 would comprise oxidized histidine species under the disclose production, storage and or in vivo conditions. One of ordinary skill in the art would have been motivated to recognize such oxidized species because histidine oxidation is associated with protein production, processng and storage including under stressed conditions and air contact, and further teaches that proteins expressed in vivo may oxidize under stressed conditions. The claimed 2-oxo-histidine species therefore represents the predictable result of subjecting the known histidine containing protein to the oxidative conditions taught in the prior art.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 15-22, 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11505594 in view of Bridgewater (see above reference). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 15 claims an aqueous composition comprising a VEGF mini trap with the Fc domain removed (see claim 15); and one or more oxidized histidines resulting in 2-oxo histidine (see claim 15).
Claims 15-22, 24 claim product by process steps. The recited process limitations are product by process limitations and patentability is determined based on the product itself rather than the process by which the product is made (see MPEP 2113). The prior art teaches the same VEGF mini trap product. Accordingly, where the claimed and prior art products are identical, the claimed product is presumed to possess the same structure and composition characteristics, notwithstanding differences in the recited method of manufacture.
US Patent No.11505594 claims a VEGF minitrap (see claim 1); wherein aflibercept was subject to proteolytic cleavage to remove the Fc domain (claim 1). US Patent No. 11505594 is silent to one or more 2-oxo-histidines (oxidative modification to histidine) but do claim oxidized species (see claim 27). However, Bridgewater teaches (at page 553) oxidization of histidine residues in peptides to 2-oxo-histidine. Bridgewater further teaches at page 555 that oxidation involves the net addition of one oxygen atom to the histidine side chain and attributes the resulting effects to 2-oxo-histidine (see page 561).
It would have been obvious before the effective filing date of the claimed invention to one of ordinary skill in the art for one or more histidine residues of the VEGF mini trap of US Patent No. ‘594 would comprise oxidized histidine species under the disclose production, storage and or in vivo conditions. One of ordinary skill in the art would have been motivated to recognize such oxidized species because histidine oxidation is associated with protein production, processing and storage including under stressed conditions and air contact, and further teaches that proteins expressed in vivo may oxidize under stressed conditions. The claimed 2-oxo-histidine species therefore represents the predictable result of subjecting the known histidine containing protein to the oxidative conditions taught in the prior art.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/ERINNE R DABKOWSKI/Primary Examiner, Art Unit 1654
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