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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 146-159 in the reply filed on 5/20/25 is acknowledged. Claims 160-165 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/20/25.
Status of Claims
Claims 146-165 are pending. Claims 160-165 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Claims 146-159 are currently under examination.
Priority
The instant application, filed 04/27/2023 is a Continuation of 17133180 , filed 12/23/2020, now abandoned
17133180 is a Continuation of 15998557 , filed 08/15/2018, now abandoned
15998557 is a National Stage entry of PCT/US2017/018233 , International Filing Date: 02/16/2017
PCT/US2017/018233 Claims Priority from Provisional Application 62296009 , filed 02/16/2016.
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 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.
Response to Arguments
Applicant's arguments filed 12/4/25 have been fully considered but they are not persuasive.
Applicant states on pages 2 to 3 that “The Office action goes on to say that it would have been obvious to combine unPEGylated and PEGylated proteins in a single composition to the trimeric H-NOX proteins taught by Cary to create a multiphasic pharmacokinetic composition comprising the H-NOX proteins with different plasma retention profiles.”
What actually is in the rejection, maintained below, is worded slightly differently, “It would have been obvious to the skilled artisan to apply the technique of combining unPEGylated and PEGylated proteins in a single composition to the trimeric H-NOX proteins taught by Cary et al. to create a multiphasic pharmacokinetic composition comprising the H-NOX proteins with different plasma retention profiles” (emphasis added).
Applicant, page 4, attacks the combination of references’ teachings by arguing that Radhakrishnan’s (or more generally also) pharmacokinetic profile does not related to applicant’s advance that includes a “simply extended” serum concentration profile and the allegedly separate “pharmacokinetic profile of the release of oxygen from the H-NOX.”
The examiner respectfully disagrees.
First, applicant’s own FIG. 3 demonstrates much greater retention in the plasma of pegylated H-NOX ((H-NOXP):
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When in the blood stream (serum) such H-NOXP is not in the tissue to release oxygen, so one would reasonably expect a more gradual release of oxygen when administering a mixture of x moles of H-NOXP and x moles of H-NOX, versus when administering 2x moles of H-NOX. Applicant’s FIG. 5 supports this:
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That is, given the much slower entry of H-NOXP versus H-NOX (this attributable to longer serum half-life, and in stating this the examiner disputes applicant’s page 4 assertion regarding lack of reasonable expectation of success), such mixture would reasonably more gradually introduce oxygen to tissue in need thereof, and a lesser extent of oxidation, such as due to too much initial oxygen, i.e., rapid reperfusion, would reasonably be expected (however please note given the claims, there is no need to get to this point, since the combined teachings already provide for the advantage of extended plasma half-life, leading to reduced dosing frequency for whatever application for which the mixture would be administered). Stated another way, the multiphasic plasma behavior reasonably and expectedly results in multiphasic entry into tissues/cells from the plasma, this resulting in what applicant terms multiphasic release of oxygen (whether multiphasic or extended is a matter of word choice in the examiner’s view, see also instant specification, para 292 page 91, stating in part, when referring to the FIG. 5 curves, “Trimeric H-NOX L144F resulted in peak oxygen delivery at about 15 min post-injection, with tissue reverting to normoxic levels until about 50 min post-injection, while PEGylated trimeric H-NOX L144F resulted in a more gradual and prolonged release of oxygen, with reversion of the hypoxic tissue to normoxic levels extending from about 200 min post-injection to at least 450 min post-injection.”
Regarding assertions on page 5, the examiner respectfully disagrees, at least because the medical effect of not increasing reactive oxygen species would be expected given less of a sharp increase in oxygen such as if only H-NOX were administered, see FIG. 5 left frame. The overall dosing of course would be critical to demonstrate any such effect – a very high dose of the 1:1 mixture would be administering so much H-NOX that a rapid initial increase in oxygen could do as much damage as half that dose just as H-NOX.
Finally, rather than FIGs. 3 and 5 which applicant on page 6 states “highlights” the difference between serum profiles and oxygen release profiles, the examiner, as explained above, perceives the serum profile differences to result in the oxygen release profiles; H-NOXP remaining in the serum longer more slowly leaves the serum to a tissue/cell, where it then can release its oxygen.
The above substantially addresses and responds to arguments made against the references applied and rejections of claims 157 and 158, in that applicants arguments against such rejections referred back to points addressed above. Please also note that the oxygen release profile in any tissue is not being claimed, and also that dosing of any oxygen carrying molecule may substantially affect oxygen delivery to a particular tissue/organ in need thereof (where delivery too rapidly or too much may be harmful, and too slow/not enough may be deleterious in a different way).
Claims 146-156 and 159 are rejected under 35 U.S.C. 103 as being unpatentable over Cary et al. (WO 2014/107171; published July 14, 2014) in view of Radhakrishnan et al. (US 2005/0095224 A1; published 2005) as evidenced by 1US Patent No. 10,766,947 B2 regarding SEQ ID NO: 8.
Cary et al. teach compositions comprising trimeric H-NOX proteins comprising three monomers, each monomer comprising a H-NOX domain from Thermoanaerobacter tengcongensis with a L144F mutation and a foldon (trimerization) domain. See para. [0032, 0245, 0246, 0252]. Cary et al. teach PEGylating the H-NOX proteins will increase the plasma retention time of the H-NOX protein. See para. [0221].
Cary et al. do not expressly teach a composition comprising a mixture of a PEGylated H-NOX protein and a non-PEGylated H-NOX protein as claimed.
The level of skill in the art is high.
The technique of combining unPEGylated and PEGylated proteins in a single composition was known in the art at the time of the effective filing date of the claimed invention. Radhakrishnan et al. combined two forms of the proteins IFN-α to create a composition that provides a multiphasic pharmacokinetic profile. See para. [0198-200]. The composition comprised an unPEGylated IFN-α and a PEGylated IFN-α. See para. [0198]. Radhakrishnan et al. teach the molar ratio of unPEGylated protein and PEGylated protein can be preselected to achieve an initial peak in the total serum concentration of the protein. See para. [0198].
It is prima face obvious to apply a known technique to improve similar products in the same way. MPEP §2143. At the time of the effective filing date of the claimed invention, the technique of combining unPEGylated and PEGylated proteins in a single composition were recognized as part of the ordinary capabilities of the one skilled in the art based. It would have been obvious to the skilled artisan to apply the technique of combining unPEGylated and PEGylated proteins in a single composition to the trimeric H-NOX proteins taught by Cary et al. to create a multiphasic pharmacokinetic composition comprising the H-NOX proteins with different plasma retention profiles. There would have been a reasonable expectation of success based on the respective teachings and examples of the references. Based on this rationale, claim 146 is rejected as obvious.
Regarding claims 147 and 148, Radhakrishnan et al. teach the molar ratio of unPEGylated protein and PEGylated protein can be preselected to achieve an initial peak in the total serum concentration of the protein. See para. [0198]. At the time of the effective filing date of the claimed invention, it would have been obvious to the artisan of ordinary skill to optimize the ratio of unPEGylated H-NOX protein and PEGylated H-NOX protein to have any appropriate ratio of unPEGylated H-NOX protein and PEGylated H-NOX protein including the claimed ratios (which in claim 147 are quite broad) in order to achieve the desired pharmacokinetic profile and plasma retention of the H-NOX protein as taught by Radhakrishnan et al.
Regarding claim 149, Cary et al. teach the amino acid sequence SEQ ID NO: 8 which is identical to the claimed amino acid sequence of SEQ ID NO: 6.
Regarding claim 150, Cary et al. teach the H-NOX domains are covalently attached to the trimerization domain. See paras. [0032, 0209, 0297].
Regarding claim 151, Cary et al. teach the C-terminus of the H-NOX domain is covalently linked to the N-terminus of the trimerization domain. See para. [0032, 0199, 0203, 0209].
Regarding claims 152 and 153, the trimerization domain comprises the sequence of SEQ ID NO: 4, GYIPEAPRDGQAYVRKDGEWVLLSTFL. SEQ ID NO: 4 taught by Cary et al. is 100% identical to the sequence set forth in the claimed SEQ ID NO: 4. See paras. [0053, 0067, 0297].
Regarding claims 154 and 155, the H-NOX monomer is attached to the trimerization domain via a Gly-Ser-Gly linker. See paras. [0032, 0209].
Regarding claim 156, Cary et al. teach the H-NOX protein domains have the amino acid sequence of SEQ ID NO: 8. See paras. [0029, 0030, 0033, 0062]. The amino acid sequence of SEQ ID NO: 8 of Cary et al. and the claimed SEQ ID NO: 8 are identical as evidenced by US Patent No. 10,766,947 B2.
Regarding claim 159, Cary et al. teach compositions that comprise pharmaceutically acceptable carriers or excipients. See paras. [0030, 0164, 0165, 0264].
Therefore, at the time of the effective filing date of the claimed inventions, claims 146-156 and 159 were prima facie obvious to the artisan of ordinary skill.
Claims 157 and 158 are rejected under 35 U.S.C. 103 as being unpatentable over Cary et al. (WO 2014/107171; published July 14, 2014) in view of Radhakrishnan et al. (US 2005/0095224 A1; published 2005) as applied to claim 146 above, and in further view of Veronese & Mero, Biodrugs, 2008, pp. 315-329, 2008 (Veronese).
The teachings of Cary et al. and Radhakrishnan et al. are discussed above. Cary et al. and Radhakrishnan et al. do not teach each monomer comprises three PEG molecules (claim 157) and the PEG molecules have a molecular weight of 5 kDa.
According to the teachings of Veronese, it is clear that the size of the polymer plays a significant role in determining the biological behavior of PEG conjugates. See page 320, right col.-§4.1, 1st paragraph. Veronese teach the only polyethylene glycol polymer used for years was 5 kDa in size and end-capped at one side with a methoxyl group and terminated with a hydroxyl group. See page 320, right col.-§4.1, 1st paragraph. Veronese teach the choice is based on the fact that the polymer is easy to activate and conjugation can be achieved in biological laboratories and not just by skilled polymer chemists. See page 320, right col.-§4.1, 1st paragraph. Veronese further teach the mass of the bound PEG is important for determining the time it remains in the blood and that the required mass can be reached by adding either several small PEG chains to the protein or alternatively one PEG chain of high mass. See page 320, right col.-§4.1, 1st paragraph.
At the time of the effective filing date, it would have been obvious to the artisan of ordinary skill to add three PEG chains of 5 kDa to each H-NOX monomer taught by Cary et al. Based on the knowledge in the art as clearly identifiable in Veronese, the size and number of units of PEG are recognized as result-effective variables amenable to routine optimization, see MPEP 2144.05. The artisan would optimize the number of PEG molecules on each monomer to have any appropriate number of PEG molecules, including the claimed three PEG molecules, in order to achieve an optimal and desired pharmacokinetic profile with the appropriate retention of the H-NOX protein in plasma. The artisan would have been motivated to use a 5kDa PEG molecule because it is taught by Veronese to be easy to activate and conjugation can be achieved in biological laboratories and not just by skilled polymer chemists as taught by Veronese There would have been a reasonable expectation of success given the knowledge in the art across a range of applications for therapeutic peptides and proteins.
Therefore, at the time of the effective filing date of the claimed inventions, the claims were prima facie obvious to the artisan of ordinary skill.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Response to Arguments
Applicant's arguments filed 12/4/25 have been fully considered but they are not persuasive.
Applicant’s statements on page 7 that “Applicant will address the obviousness double patenting rejection[s], to the extent necessary, upon an indication that the claims are otherwise in condition for allowance” are neither substantive nor effective responses to the rejections, maintained below.
Claims 146-156 and 159 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 13, 18 and 21 of U.S. Patent No. 10385116 (Reference patent) in view of Radhakrishnan et al. (US 2005/0095224 A1; published 2005).
Reference patent claim 1 claims a trimeric H-NOX protein comprising three monomers, each monomer comprising a H-NOX domain from Thermoanaerobacter tengcongensis with a L144F substitution and a trimerization domain.
Reference patent claim 19 claims each of the three H-NOX monomers is PEGylated.
Reference patent claims do not claim a mixture of a PEGylated H-NOX protein and a non-PEGylated H-NOX protein as instantly claimed in instant claim 146.
The level of skill in the art is high.
The technique of combining unPEGylated and PEGylated proteins in a single composition was known in the art at the time of the effective filing date of the claimed invention. Radhakrishnan et al. combined two forms of the proteins IFN-α to create a composition that provides a multiphasic pharmacokinetic profile. See para. [0198-200]. The composition comprised an unPEGylated IFN-α and a PEGylated IFN-α. See para. [0198]. Radhakrishnan et al. teach the molar ratio of unPEGylated protein and PEGylated protein can be preselected to achieve an initial peak in the total serum concentration of the protein. See para. [0198].
It is prima face obvious to apply a known technique to improve similar products in the same way. MPEP §2143. At the time of the effective filing date of the claimed invention, the technique of combining unPEGylated and PEGylated proteins in a single composition were recognized as part of the ordinary capabilities of the one skilled in the art based. It would have been obvious to the skilled artisan to apply the technique of adding unPEGylated H-NOX trimeric protein to the Reference patent claim 19 PEGylated H-NOX trimeric proteins to form a single composition, this a pharmaceutical composition given the components, to create a multiphasic pharmacokinetic composition comprising the H-NOX proteins with different plasma retention profiles. Once There would have been a reasonable expectation of success based on the respective teachings and examples of the references. Based on this rationale, claim 146 is rejected under this section.
Regarding claims 147 and 148, Radhakrishnan et al. teach the molar ratio of unPEGylated protein and PEGylated protein can be preselected to achieve an initial peak in the total serum concentration of the protein. See para. [0198]. At the time of the effective filing date of the claimed invention, it would have been obvious to the artisan of ordinary skill to optimize the ratio of unPEGylated H-NOX protein and PEGylated H-NOX protein to have any appropriate ratio of unPEGylated H-NOX protein and PEGylated H-NOX protein including the claimed ratios (which in claim 147 are quite broad) in order to achieve the desired pharmacokinetic profile and plasma retention of the H-NOX protein as taught by Radhakrishnan et al.
Regarding claim 149, Reference patent claim 21 claims the amino acid sequence SEQ ID NO: 8, which is identical to the instantly claimed amino acid sequence of SEQ ID NO: 6.
Regarding claims 150 and 151, Reference patent claim 2 claims the C-terminus of H-NOX domain is covalently attached to the trimerization domain.
Regarding claim 152, Reference patent claim 1 claims that the trimerization domain in each H-NOX monomer is a foldon domain of bacteriophage T4 fibritin.
Regarding claim 153, the foldon domain of bacteriophage T4 fibritin, as claimed in Reference patent claim 1, comprises the sequence of SEQ ID NO: 4, GYIPEAPRDGQAYVRKDGEWVLLSTFL, as defined in its specification at para 54, and this SEQ ID NO: 4 of the Reference patent is 100% identical to the sequence set forth in the claimed SEQ ID NO: 4.
Regarding claims 154 and 155, Reference patent claim 18 claims a linker and Reference patent claim 22 specifies this linker as a Gly-Ser-Gly linker.
Regarding claim 156, Reference patent claim 21 claims the amino acid sequence SEQ ID NO: 8, which is identical to the instantly claimed amino acid sequence of SEQ ID NO: 6.
Regarding claim 159, Reference patent claim 13 claims a pharmaceutical composition that comprises pharmaceutically acceptable carriers or excipients.
Therefore, at the time of the effective filing date of the claimed inventions, claims 146-156 and 159 are rejected under this section.
Claims 157 and 158 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10385116 in view of Radhakrishnan et al. (US 2005/0095224 A1; published 2005), as applied to claim 146 above, and in further view of Veronese & Mero, Biodrugs, 2008, pp. 315-329, 2008 (Veronese).
The rejections based on the Reference patent claims and Radhakrishnan et al. are set forth above. The indicated Reference patent claims and Radhakrishnan et al. do not teach each monomer comprises three PEG molecules (claim 157) and the PEG molecules have a molecular weight of 5 kDa.
According to the teachings of Veronese, it is clear that the size of the polymer plays a significant role in determining the biological behavior of PEG conjugates. See page 320, right col.-§4.1, 1st paragraph. Veronese teach the only polyethylene glycol polymer used for years was 5 kDa in size and end-capped at one side with a methoxyl group and terminated with a hydroxyl group. See page 320, right col.-§4.1, 1st paragraph. Veronese teach the choice is based on the fact that the polymer is easy to activate and conjugation can be achieved in biological laboratories and not just by skilled polymer chemists. See page 320, right col.-§4.1, 1st paragraph. Veronese further teach the mass of the bound PEG is important for determining the time it remains in the blood and that the required mass can be reached by adding either several small PEG chains to the protein or alternatively one PEG chain of high mass. See page 320, right col.-§4.1, 1st paragraph.
At the time of the effective filing date, it would have been obvious to the artisan of ordinary skill to add three PEG chains of 5 kDa to each H-NOX monomer claimed in Reference patent claim 19. Based on the knowledge in the art as clearly identifiable in Veronese, the size and number of units of PEG are recognized as result-effective variables amenable to routine optimization, see MPEP 2144.05. The artisan would optimize the number of PEG molecules on each monomer to have any appropriate number of PEG molecules, including the claimed three PEG molecules, in order to achieve an optimal and desired pharmacokinetic profile with the appropriate retention of the H-NOX protein in plasma. The artisan would have been motivated to use a 5kDa PEG molecule because it is taught by Veronese to be easy to activate and conjugation can be achieved in biological laboratories and not just by skilled polymer chemists as taught by Veronese There would have been a reasonable expectation of success given the knowledge in the art across a range of applications for therapeutic peptides and proteins.
Therefore, claims 157 and 158 are rejected under this section.
Conclusion
No claim is allowed.
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 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 Monday/Tuesday and on Wednesday-Friday on alternating weeks, but will promptly answer messages upon his return to work.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached on 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658
1 US Patent No. 10,766,947 B2; published 2020
Prosecution Insights