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 . 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.
Election/Restrictions
Applicants elected IgG attached to insulin via a PEG chain without traverse in the reply filed on 25 Sept, 2023. In the response of 29 Nov, 2024, the claims were amended so as to no longer read on this species.
Claims Status
Claim 1 is pending.
Claim 1 has been amended.
Maintained/Modified Rejections
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.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Song et al (US 20120003712, referred to as Song1 in this rejection) in view of Song et al (US 20130028918, previously presented, referred to as Song2 in this rejection) and Patel et al (Bioprocess Int. (2011, previously presented).
Song1 discusses a method of site specifically modifying a polypeptide (title), which is preferably insulin, exendin-4, oxyntomodulin, or derivatives (paragraph 52). A preferred derivative is des-aminohistidyl extendin-4, or imidazolacetyl-exendin-4 (paragraph 66). There are several examples of reacting di-propionaldehyde PEG with imidazo-acetyl exendin-4 followed by purification by ion exchange (examples 2-6, paragraphs 88-92). This was then coupled with an immunoglobulin Fc fragment, followed by purification (paragraph 93).
The difference between this reference and the examined claims is that this reference uses different excipients and pH for the final solution, and does not mention an aglycosylated Fc.
Song2 discusses linking insulin with an immunoglobulin Fc region via a non-peptidyl polymer (paragraph 16), identically with Song1. Paragraph 32 of Song2 discusses IgG Fc regions, applicant’s elected Fc region. PEG is listed as a non-peptidyl polymer that can be used (paragraph 46), applicant’s elected non-peptidyl polymer. Human Fc regions are mentioned as preferable (paragraph 37), including IgG4 subclass (paragraph 43). Aglycosylated Fc domains are suggested as being more suitable as less immunogenic (paragraph 38). Formulations including mannitol are mentioned (paragraph 54). An embodiment of the invention comprises reacting a non-peptidyl polymer with insulin, isolating the conjugate, then linking the conjugate to an immunoglobulin Fc region (paragraphs 66-69). Examples are purified using chromatography, and tests were run at pH 4.5 and 7.5 (paragraphs 83 and 84). Note that this is the pH range that the material is described as being effective (paragraph 27), and is presumably the pH that any formulation would use. This reference describes in more detail an embodiment of the invention of Song1.
Patel et al discuss stabilizing polypeptide formulations (title). They often remain stable in only a limited pH range (1st page, 2nd paragraph). Mannitol can reduce oxidation by scavenging metal catalysts (7th page, 2nd paragraph), and methionine can be used as an antioxidant (7th page, 2nd paragraph). Polysorbates, including polysorbate 80, can reduce aggregation (13th page, 2nd paragraph). This reference teaches that pH control, mannitol, and polysorbates can increase polypeptide stability.
Therefore, it would be obvious to use the aglycosylated Fc domain of Song2 for the coupling of Song1, to produce an embodiment that was less immunogenic. As Song2 is a specific embodiment of Song1, an artisan in this field would attempt this substitution with a reasonable expectation of success.
Furthermore, it would be obvious to optimize the pH to optimize the stability of the formulation, as Patel et al mentions that pH can affect the stability. The MPEP states that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.”) (MPEP2144.05.II).
Finally, it would be obvious to add the mannitol, methionine, and polysorbate of Patel et al to the formulation, to enjoy the stability that these excipients provide. As Patel et al is generic for the polypeptide, an artisan in this field would attempt this addition with a reasonable expectation of success.
response to applicant’s arguments
Applicants argue that the pH of Song2 is conjugation, not formulation, that the polypeptides without modification have low solubility at the claimed pH, that Song2 et al discusses insulin conjugates rather than the claimed polypeptides, and that the rationale for using an aglycosylated Fc region is different than applicants.
Applicant's arguments filed 29 Oct, 2025 have been fully considered but they are not persuasive.
Applicants argue that the pH of Song2 is conjugation. This is not correct; the two places cited in the rejection deal with in vivo and in vitro experiments. In addition, as noted in the rejection, it is common in the art to optimize pH in polypeptide formulations to maximize stability.
Applicants argue that the unmodified polypeptides of the claims have low solubility at the claimed pH. Applicants have not provided any explanation as to why this fact overcomes the rejection, nor is it clear on its face.
Applicants argue that the Song2 discusses insulin conjugates rather than the claimed polypeptides. This is an argument of non-analogous art. For a reference to be analogous, it must be either in the same field of endeavor as the claimed invention, or reasonably pertinent to the problem faced by the inventor (MPEP 2141.01(a)(I)). As this reference anticipated applicant’s claims in the first office action, it is in the same field of endeavor as the claimed invention, so is analogous art.
Finally, applicants argue that the rationale for using aglycosylated material in the rejection is different than the rationale that applicants are using. However, there is no requirement that the rationale used in a rejection be the same one used by applicants (MPEP 2144(IV)).
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.
first rejection
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 8 of copending Application No. 18/040,869 (US 20230302148) (previously cited) in view of Song et al (US 20130028918, previously presented), and Patel et al (Bioprocess Int. (2011).
Competing claim 1 describes a formulation of a polypeptide that binds to the glucagon receptor where the polypeptide is selected from a Markush group that includes SEQ ID 11, which is CA-exendin-4, attached to an Fc region via a PEG linker. Competing claim 8 specifies that the Fc region is from IgG.
The difference between the competing claims and the examined claims is that the competing claims do not discuss the synthesis and the final formulation.
Song et al discusses linking insulin (applicant’s elected therapeutic) with an immunoglobulin Fc region via a non-peptidyl polymer (paragraph 16) to improve in vivo duration and stability (abstract). An embodiment of the invention comprises reacting a non-peptidyl polymer with insulin, isolating the conjugate, then linking the conjugate to an immunoglobulin Fc region (paragraphs 66-69). Human Fc regions are mentioned as preferable (paragraph 37), including IgG4 subclass (paragraph 43). Aglycosylated Fc domains are suggested as being more suitable (paragraph 38).
Patel et al discuss stabilizing polypeptide formulations (title). They often remain stable in only a limited pH range (1st page, 2nd paragraph). Mannitol can reduce oxidation by scavenging metal catalysts (7th page, 2nd paragraph), and methionine can scavenge oxidants (7th page, 2nd paragraph). Polysorbates can reduce aggregation (13th page, 2nd paragraph). This reference teaches that pH control, mannitol, and polysorbates can increase polypeptide stability.
Therefore, it would be obvious to substitute the unspecified reaction protocol of the competing claims with the protocol of Song et al yielding the expected result of a coupling, to improve in vivo duration and stability. As the reactions of Song et al are very general, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to optimize the pH to optimize the stability of the formulation, as Patel et al mentions that pH can affect the stability. The MPEP states that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); 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.”) (MPEP2144.05.II).
Finally, it would be obvious to add the mannitol, polysorbate, and methionine of Patel et al to the formulation, to enjoy the stability that these excipients provide. As Patel et al is generic for the polypeptide, an artisan in this field would attempt this addition with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
response to arguments
Applicants have referenced the arguments with respect to the rejection under 35 USC 103, which were answered there.
Additional Rejections
Claim 1 is rejected on the grounds of non-statutory double patenting as being unpatentable over copending Applications No. 17/866,188 17/730,510, 18/269,134 or copending patents US 11,872,283 11,603,346 11,123,436 10,660,940 10,487,128 10,441,665 10,159,715 9,833,516 9,801,950 9,636,420 10,071,171 8,263,084 12,139,455 or 7,736,653 in view of Song et al (US 20130028918, previously presented) and Patel et al (Bioprocess Int. (2011).
The teachings of the competing applications and patents and the logic of the rejections follow similarly to the double patenting rejections above.
response to arguments
Applicants have referenced the arguments with respect to the rejection under 35 USC 103, which were answered there.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658