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 .
Priority
The instant application, filed 5/28/24, is a DIV of 17526203, filed 11/15/2021 Claims Priority from Provisional Application 63114044 , filed 11/16/2020.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 5/28/24 Information Disclosure Statement, and provides a signed and dated copy of such herewith.
Claim Status
Claims 1-6 are pending and under examination.
Claims 1-6 are rejected.
Claim Interpretation
The claim limitations are given their broadest reasonable interpretation (BRI) consistent with the specification, MPEP 2111, and under the BRI, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification, MPEP 2111.01.
The transition phrase “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps, see MPEP 2111.03 I.
However, the use of “consists of” in claim 1 in reference to the aFGF protein limits the protein to only have the amino acid sequence of SEQ ID NO:1, not more, not less. See MPEP 2111.03 II.
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) 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over US 7956033, Cheng and Kuo, issued 6/7/2011 (CK), in view of US 5120715, Kato et al., issued 6/9/1992 (Kato), as evidenced by Mohan, Buffers, Calbiochem, 37 pages 2003 (Mohan, provided in 5/28/24 IDS so copy not provided).
Claim 1 is directed to a method for improving stability of an acidic fibroblast growth factor (aFGF) protein, comprising formulating the aFGF protein in a citrate buffer to obtain a liquid formulation, wherein the aFGF protein consists of the amino acid sequence of SEQ ID NO.: 1.
Claim 2 depends from claim 1 and requires the citrate buffer comprising citric acid or isocitric acid.
Claim 3 depends from claim 1 and requires “further comprising lyophilizing the liquid formulation.”
CK teaches a modified peptide of human acidic fibroblast growth factor (aFGF), comprising a native human aFGF shortened by a deletion of a deletion of 20 amino acids from N-terminal of the native human aFGF, and an addition of Alanine (Ala) before the shortened native aFGF, Abstract.
This modified aFGF is admitted as the same as instant SEQ ID NO:1, see instant specification, para 36, and meets the elected species of aFGF.
CK does not teach this aFGF in a pharmaceutical composition with a citric acid compound as required by claim 1.
The level of ordinary skill in the art is high and motivated to improve existing formulations by modifying them with known approaches to improvement, including improvement of stability.
Kato teaches that its fibroblast growth factor (FGF) proteins includes both acidic and basic FGFs, col. 1 lines 13-20, col. 2 lines 30-33, and Kato teaches that its FGF protein-containing solutions are mainly composed of water, and are adjusted to pH between about 3 to about 10 with buffer solutions such as phosphate buffer, citrate buffer and Tris-HCl buffer “to prevent inactivation of the FGFs”, col. 5 lines 37-53.
Kato also teaches that its FGF protein is formed into pharmaceutical compositions, col. 6, lines 32-36, and also pertaining to the elected lyophilized formulation and claim 3, Kato generally teaches lyophilized products per paras 55-56.
Because a combination of the same components would have the same properties, Kato additionally teaches that combining its FGFs, which encompass aFGF, with citrate buffer to prevent inactivation of the FGFs (whether prior to, during and/or after lyophilization), this supports the resultant aqueous solutions of Kato having improved stability.
It would have been obvious to modify the pharmaceutical formulations of CK that comprise instant SEQ ID NO:1 by adding a citrate buffer comprising citric acid to prevent FGF inactivation. The motivation is to improve stability of a pharmaceutical formulation by using a known approach, adding a known buffer, taught to provide stability improvement of FGFs (taught by Kato to include aFGFs).
There would have been a reasonable expectation of success given the teachings of CK and Kato.
Accordingly, claims 1 and 3 would have been obvious.
As to claim 2, as evidenced by Mohan, page 19, citrate buffer comprises citric acid and sodium citrate dihydrate, so that in view of the references’ teachings claim 2 would have been obvious.
Claim(s) 3-6 are rejected under 35 U.S.C. 103 as being unpatentable over US 7956033, Cheng and Kuo, issued 6/7/2011 (CK), in view of US 5120715, Kato et al., issued 6/9/1992 (Kato) and US 2012/0121580, Bhambhani et al., Assignee Merck Sharp & Dohme Corp., published 5/17/2012 (Bhambhani), as evidenced by Mohan, Buffers, Calbiochem, 37 pages 2003 (Mohan, provided in 5/28/24 IDS so copy not provided).
The rejection of claims 1 and 3 over CK and Kato as evidenced by Mohan are set forth above.
Claim 3 depends from claim 1 and requires “further comprising lyophilizing the liquid formulation.”
Claim 4 depends from claim 3 and requires that the liquid formulation further comprises a mannitol, a sugar or both, and claim 5 depends from claim 4 and lists as the sugar trehalose, sucrose, and the combination thereof.
Claim 6 depends from claim 3 and requires that the liquid formulation further comprises mannitol and trehalose.
The level of ordinary skill in the art is high and motivated to improve existing formulations by modifying them with known approaches to improvement, including improvement of stability. This includes regarding preparation of lyophilized protein/peptide formulations directed to protect active agents during the lyophilization process and also during subsequent storage.
Whereas Kato only briefly recites lyophilized products, Bhambhani focuses on these, including specific additives and combinations thereof.
Bhambhani teaches methods of producing lyophilized pharmaceutical compositions comprising a high concentration of therapeutic protein (or antibody) prior to lyophilization, wherein the lyophilized formulation can be reconstituted with a diluent in about 15 minutes or less, and also high concentration lyophilized formulations produced by its methods, these formulations taught to be stable and suitable for veterinary and human medical use and suitable for various common modes of administration, and also having long term stability, Abstract.
Bhambhani claim 1 teaches
A high concentration pharmaceutical composition comprising:
(i) about 70-250 mg/ml of antibody or about 5 mg/ml to about 60 mg/ml of therapeutic protein or peptide;
(ii) about 1% to about 6% w/v sucrose or trehalose;
(iii) about 25 mM to about 100 mM histidine, succinate or bis-tris;
(iv) about 25 mM to about 100 mM arginine; and
(v) about 3% to about 8% w/v mannitol,
wherein the pH of the composition is about 5.5 to about 7.5 and wherein the composition does not comprise hydrochloric acid.
Bhambhani specification also teaches amounts and ranges of protein, mannitol, and sucrose, compared below to claim 1 of Bhambhani, and includes comments about citrate:
Bhambhani Claim 1 ranges
Relevant Bhambhani Specification teachings
Comment
Therapeutic Protein
5-60 mg/mL
Sucrose
1-6% w/v
Paragraph 66 recites ranges including about 1% to about 3% sucrose or trehalose, and the paragraph ends with a preference statement, “In some
preferred embodiments of this aspect of the invention, the composition described above comprises about 3% w/v sucrose.”
Mannitol
3-8% w/v
Paragraph 69 recites ranges including about 3% to about 8% mannitol, and the paragraph ends with a preference statement, “In some preferred embodiments of this aspect of the invention, the compositions described about comprise about 5% w/v mannitol.”
Citrate
Sheet 1 Fig. 1 lists two formulations with citrate-phosphate buffer
Para 94 also lists citrate-phosphate buffer, results on page 12, Table 1,
Para 96 lists sodium citrate among stabilizers or solubilizers, also listed I para 106
Also in claim 8
These noted statements in the indicated paragraphs for sucrose and mannitol values set forth a strong suggestion to evaluate as a starting point, and/or utilize, both sucrose and mannitol when preparing a protein formulation for lyophilized form. Bhambhani also recites the uses of citrate.
Based on Bhambhani’s claim 1 language using mg/ml, this indicates an aqueous solution, and elsewhere Bhambhani teaches that its formulations as aqueous solutions are lyophilized to remove water, see for example Title, Abstract, Figs. 24A, 24B, and Summary of the Invention at paragraphs 10, 11 and 17-24. Accordingly, based on Bhambhani’s overall teachings, both sucrose and mannitol would reasonably be used in lyophilized formulations with a protein such as the aFGF of CK, and reasonably combined with citrate buffer to prevent inactivation of the FGFs.
Given the particular teachings including statements of preferences for particular values and ranges when presenting multiple ranges, as to claims 10 and 11 Bhambhani establishes a prima facie case of obvious for the use of sucrose and mannitol in lyophilized formulations for therapeutic proteins.
Additionally given the recitation of citrate in Bhambhani, and the teaching in Kato that buffer solutions such as phosphate buffer, citrate buffer and Tris-HCl buffer “to prevent inactivation of the FGFs”, col. 5 lines 37-53, and as evidenced by Mohan, page 19, that citrate buffer comprises citric acid and sodium citrate dihydrate, and also that citrate-phosphate buffer comprises citric acid, page 20, one of ordinary skill in the art would have been motivated to provide citric acid in some form of buffer or additive to further maintain stability of FGFs, by preventing their inactivation, and also would have been motivated to compare the results of such citric acid content excipients with the histidine, succinate or bis-tris also taught by Bhambhani.
There would have been a reasonable expectation of success given the known sequence of steps toward developing a lyophilized formulation comprising the aFGF therapeutic protein of CK in view of the teachings of Bhambhani and Kato.
Accordingly claims 3-6 would have been obvious.
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 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 7956033 (“reference patent”) in view of US 5120715, Kato et al., issued 6/9/1992 (Kato) and US 2012/0121580, Bhambhani et al., Assignee Merck Sharp & Dohme Corp., published 5/17/2012 (Bhambhani), as evidenced by Mohan, Buffers, Calbiochem, 37 pages 2003 (Mohan, provided in 5/28/24 IDS so copy not provided).
The instant claims are set forth above.
The reference patent claim 1 is directed to a modified peptide of human acidic FGF consisting of the amino acid sequence of SEQ ID NO:1, and reference patent claim 2 is directed to a pharmaceutical composition comprising the claim 1 modified peptide and a pharmaceutically acceptable carrier.
The reference patent claims are silent as to what carriers are in its claim 2 pharmaceutical composition, however from the teachings of Kato - that its fibroblast growth factor (FGF) proteins includes both acidic and basic FGFs, col. 1 lines 13-20, col. 2 lines 30-33, that its FGF protein-containing solutions are mainly composed of water, and are adjusted to pH between about 3 to about 10 with buffer solutions such as phosphate buffer, citrate buffer and Tris-HCl buffer “to prevent inactivation of the FGFs”, col. 5 lines 37-53, one or ordinary skill in the art reasonably would have added citrate buffer from Kato’s short list of three buffer solutions to prevent inactivation of FGFs, motivated by the interest to provide a more stable and usable pharmaceutical composition. As evidenced by Mohan, page 19, citrate buffer comprises citric acid and sodium citrate dihydrate.
Kato also teaches that its FGF protein is formed into pharmaceutical compositions, col. 6, lines 32-36, and also pertaining to the elected lyophilized formulation and claim 9, Kato generally teaches lyophilized products per paras 55-56.
Whereas Kato only briefly recites lyophilized products, Bhambhani focuses on these, including specific additives and combinations thereof.
Bhambhani teaches methods of producing lyophilized pharmaceutical compositions comprising a high concentration of therapeutic protein (or antibody) prior to lyophilization, wherein the lyophilized formulation can be reconstituted with a diluent in about 15 minutes or less, and also high concentration lyophilized formulations produced by its methods, these formulations taught to be stable and suitable for veterinary and human medical use and suitable for various common modes of administration, and also having long term stability, Abstract.
Bhambhani claim 1 teaches
A high concentration pharmaceutical composition comprising:
(i) about 70-250 mg/ml of antibody or about 5 mg/ml to about 60 mg/ml of therapeutic protein or peptide;
(ii) about 1% to about 6% w/v sucrose or trehalose;
(iii) about 25 mM to about 100 mM histidine, succinate or bis-tris;
(iv) about 25 mM to about 100 mM arginine; and
(v) about 3% to about 8% w/v mannitol,
wherein the pH of the composition is about 5.5 to about 7.5 and wherein the composition does not comprise hydrochloric acid.
Bhambhani specification also teaches amounts and ranges of protein, mannitol, and sucrose, compared below to claim 1 of Bhambhani, and includes comments about citrate:
Bhambhani Claim 1 ranges
Relevant Bhambhani Specification teachings
Comment
Therapeutic Protein
5-60 mg/mL
Sucrose
1-6% w/v
Paragraph 66 recites ranges including about 1% to about 3% sucrose or trehalose, and the paragraph ends with a preference statement, “In some
preferred embodiments of this aspect of the invention, the composition described above comprises about 3% w/v sucrose.”
Mannitol
3-8% w/v
Paragraph 69 recites ranges including about 3% to about 8% mannitol, and the paragraph ends with a preference statement, “In some preferred embodiments of this aspect of the invention, the compositions described about comprise about 5% w/v mannitol.”
Citrate
Sheet 1 Fig. 1 lists two formulations with citrate-phosphate buffer
Para 94 also lists citrate-phosphate buffer, results on page 12, Table 1,
Para 96 lists sodium citrate among stabilizers or solubilizers, also listed I para 106
Also in claim 8
These noted statements in the indicated paragraphs for sucrose and mannitol values set forth a strong suggestion to evaluate as a starting point, and/or utilize, both sucrose and mannitol when preparing a protein formulation for lyophilized form. Bhambhani also recites the uses of citrate.
Based on Bhambhani’s claim 1 language using mg/ml, this indicates an aqueous solution, and elsewhere Bhambhani teaches that its formulations as aqueous solutions are lyophilized to remove water, see for example Title, Abstract, Figs. 24A, 24B, and Summary of the Invention at paragraphs 10, 11 and 17-24. Accordingly, based on Bhambhani’s overall teachings, both sucrose and mannitol would reasonably be used in lyophilized formulations with a protein such as the aFGF of the reference patent claims, and reasonably combined with citrate buffer to prevent inactivation of the FGFs.
Given the particular teachings including statements of preferences for particular values and ranges when presenting multiple ranges, as to claims 10 and 11 Bhambhani establishes a prima facie case of obvious for the use of sucrose and mannitol in lyophilized formulations for therapeutic proteins.
Additionally given the recitation of citrate in Bhambhani, and the teaching in Kato that buffer solutions such as phosphate buffer, citrate buffer and Tris-HCl buffer “to prevent inactivation of the FGFs”, col. 5 lines 37-53, and as evidenced by Mohan, page 19, that citrate buffer comprises citric acid and sodium citrate dihydrate, and also that citrate-phosphate buffer comprises citric acid, page 20, one of ordinary skill in the art would have been motivated to provide citric acid in some form of buffer or additive to further maintain stability of FGFs, by preventing their inactivation, and also would have been motivated to compare the results of such citric acid content excipients with the histidine, succinate or bis-tris also taught by Bhambhani.
There would have been a reasonable expectation of success given the known sequence of steps toward developing a lyophilized formulation comprising the aFGF therapeutic protein of the reference patent in view of the teachings of Bhambhani and Kato.
Accordingly claims 1-6 are rejected under this section.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH FISCHER whose telephone number is (571)270-7925. The examiner can normally be reached on Monday to Friday, 9:00 AM to 5:00 PM, however noting that the examiner will not normally be working on Wednesday-Friday and on Monday/Tuesday on alternating weeks, but will promptly answer messages upon his return to work.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658
