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
Applicant's election with traverse of cyclizing a peptide with PyOxim with diafiltration in the reply filed on 16 March, 2026 is acknowledged. The traversal is on the ground(s) that there is no listing of distinct species, insufficient justification, no showing of distinctness, and no demonstration of lack of unity. This is not found persuasive because applicants are citing items that are not required for an election of species for an application filed under 35 USC 371.
Applicants argue that there is no listing of distinct species. They have not pointed to any law, regulation, or court case that requires that every possible species be listed. Indeed, claim 16 is written so generally that the only limitation of the reactants is that they react with each other. This is an infinite list, which would be impossible to list item by item.
Applicants argue that there is no showing of distinctness. As applicants have filed their application under 35 USC 371, there is no requirement for a showing of distinctness (MPEP 1893.03(d)). Applicants argue there is no showing of a lack of unity. That is required for a restriction, but not for an election of species (MPEP 1893.03(d)).
The requirement is still deemed proper and is therefore made FINAL.
It is noted that PyOxim is a reagent used to form an amide bond from a carboxylate and an amine. This is not a metastable product, so the election of species is interpreted as using the reagent to cyclize a peptide sequence. In addition, applicants have not described a metastable rearrangement in response to the election of species requirement
Applicants have elected using PyOxim to form a cyclic peptide with diafiltration. A search was conducted for this invention, and references rendering it obvious were found. As a result, claims 16-20, 24, 25, and 27-30 have been examined and claims 21-23 and 26 have been withdrawn from consideration. Applicants have stated that they believe all claims read on the elected species, but claims 21 and 22 describe a metastable product of a first reaction. As noted above, applicant’s elected reaction is an amide coupling reaction, which is not metastable, so these claims are properly withdrawn. Claim 23 specifies additional reactions with additional reagents that applicants have not elected. Competing claim 26 specifies a filtration system different than the elected diafiltration.
During examination, a reference was discovered that anticipated or rendered obvious at least one claim. This reference is discussed below.
Claims Status
Claims 16-30 are pending.
Claims 21-23 and 26 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 16 March, 2026.
Claim Rejections - 35 USC § 102/ 35 USC § 103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
The 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.
Claim(s) 16-20, 24, 27, and 28 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Ormerod et al (US 20170260229), with evidentiary support from the CP303 problem set #5 (2013).
Ormerod et al discuss reactions that must be carried out at low concentration or high dilution (paragraph 2), such as cyclization reactions (paragraph 3). The reactants are fed into a reactor at dilution to form a product, which is filtered and the solvent returned to the reactor (paragraphs 11-15). The product flows into filtration loop feed tank, from which the liquid to be filtered is drawn (paragraph 21, figs 1 and 2). This leads to reduced solvent use per unit of reaction product (paragraph 10). The solvent used is not limited, with a number of organic solvents mentioned (paragraph 88). Note that experiments with the system lead to 100% conversion rate (table 2, paragraph 173). As evidenced by the CP3030 problem set, the relationship between volume of a CSTR (such as used by Ormerod et al) and the conversion is V=FoX/-r (equation 5.7, middle of 2nd page), where V is the volume of the reactor, Fo is the molar feed rate, and -r is the reaction rate. Note that -r is almost always a power of the outlet concentration of the starting material: for a first order reaction, -r=kCf, a second order reaction -r=KCf1Cf2. For X=1, the concentration of the material leaving the reactor must be zero; it must have all reacted. However, for the CSTR, that means that the volume must be infinite, which is physically impossible. However, as Ormerod et al show reactions that lead to 100% conversion, the material must continue to react in the filtration loop feed tank; so the reactor is both the reactor and the feed tank. This means that the flow of the filter retentate back into the filtration loop feed tank meets the limitation of the claims that the first and third compounds be retained in the reactor, anticipating claim 16. Alternatively, the point of separating out the product in a separate tank, rather than recycling to the reactor, is to prevent further reaction in the reactor (paragraph 133). With a product that does not further react under the reaction conditions, it is obvious to recycle it back to the reactor, rendering obvious claim 16. With constant addition, the concentration of the substrate is kept stable (paragraph 90), anticipating or rendering obvious claim 17. The filtrate is returned to the reaction vessel, as noted above, anticipating or rendering obvious claim 18. The rate of material added to the reactor is matched to the amount of material removed (paragraph 127), which would keep the volume constant, anticipating or rendering obvious claim 19. Filtration is typically accomplished with diafiltration (paragraph 115), anticipating or rendering obvious claim 20. An example was conducted where 1-desamino-8d-Arg was cyclized (paragraph 178); note that this compound comprises Tyr, which has a hydroxyl group, anticipating or rendering obvious claims 24 and 28. While Ormerod et al discuss the product passing through the membrane, it is clear that they envision embodiments where it does not, with 90-95% retention rate (paragraph 95), anticipating or rendering obvious claim 27.
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(s) 16-20, 24, 25, and 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over Ormerod et al (US 20170260229) in view of Albericio et al (Org. Process. Res. Dev. (2018) 22 p760-772) and the Millipore guide to ultrafiltration/diafiltration optimization (2008).
The teachings of Ormerod et al were given above, and will not be repeated here. Note that this reference anticipates or renders obvious claims 16-20, 24, 27, and 28.
The difference between this reference and the remaining claims is that this reference does not disclose the reactant ratio, a carboxyl group activating agent, or a second purification step.
Albericio et al discuss selection of the right coupling agent (title). PyOxim was demonstrated to be efficient for cyclizing a model peptide, Ala-Ala-NMeAla-Ala-Ala (p765, 2nd column, 1st paragraph). Note that the only reactive sites on that sequence are the C-terminus and the N-terminus; this is a head to tail cyclization in solution. PyOxim is their favorite coupling reagent for cyclizations, as it is powerful and exempt of side reactions (p768, 2nd column, 2nd paragraph). This reference discusses PyOxim for a cyclization reaction, one of the types of reactions that Ormerod et al state are useful in their method.
The Millipore guide to ultrafiltration/diafiltration discusses optimization of the method (title). This can be used to concentrate the final product (4th page, 1st column, point 5). It can also be used to remove contaminants (6th page, 2nd column, 2nd paragraph). This reference discusses the uses of diafiltration.
Therefore, it would be obvious to cyclize the peptides of Albericio et al with PyOxim using the system of Ormerod et al, to reduce the amount of solvent needed and to avoid polymerization reactions, as mentioned by Ormerod et al. As that reference discusses cyclization reactions, an artisan in this field would attempt this modification with a reasonable expectation of success.
Furthermore, it would be obvious to use diafiltration to concentrate the final product, as well as remove any impurities of an appropriate size, as discussed by the Millipore guide, to provide a purer product at an appropriate concentration for the next step of the process. As diafiltration is commonly used for these purposes, an artisan in this field would attempt this process with a reasonable expectation of success.
While neither reference discusses the ratio of the two compounds (the coupling agent and the peptide), in general, differences in concentration are not considered patentable distinctions, because they are routinely optimized (MPEP 2144.05(II)), rendering obvious claim 25.
Albericio et al render obvious using PyOxim to cyclize a peptide, rendering obvious claim 29 and applicant’s elected species.
The Millipore guide to diafiltration renders obvious an additional diafiltration process, rendering obvious claim 30.
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 16-20, 24, 25, 27, and 28 and 30 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 6, 8, and 15 of U.S. Patent No. 12/466,851 in view of the Millipore guide to ultrafiltration/diafiltration optimization (2008).
Competing claim 1 describes a method of cyclizing a peptide via a disulfide bond, where the concentration of the oxidant in the reaction vessel is essentially zero. Competing claim 5 specifies removal of low molecular weight species while the oxidizing agent is added to the reactor, while claim 6 specifies that this removal is done by membrane filtration. While the competing claims are silent about returning the higher molecular weight compounds to the reactor, there is no obvious reason to put that stream elsewhere. Competing claim 8 describes further purification of the final product. Competing claim 15 specifies that the amount of oxidizer is controlled by monitoring the redox potential of the reactor (i.e., with the essentially zero limitation of claim 1, this is essentially constant).
The difference between the competing claims and the examined claims is that the competing claims do not specify the final purification method.
The Millipore guide to ultrafiltration/diafiltration discusses optimization of the method (title). This can be used to concentrate the final product (4th page, 1st column, point 5). It can also be used to remove contaminants (6th page, 2nd column, 2nd paragraph). This reference discusses the uses of diafiltration.
Therefore, it would be obvious to use diafiltration as the final purification step, to also adjust the concentration to an appropriate level for whatever the next step may be. As diafiltration is common in the art, an artisan in this field would attempt this process with a reasonable expectation of success.
Conclusion
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658