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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 16, 2026 has been entered.
Election/Restrictions
Applicant’s election with traverse of Group I, comprising claims 1-6, 9-14, and 17-20 in the reply filed on November 20, 2024 is acknowledged.
Although the inventions of Groups I and II do not share a special technical feature and Applicant’s arguments are not persuasive because the independent claim does not require an Fc region or PEGylation, upon further examination prior art found applicable to the elected invention of Group I was found to be applicable to Group II, and therefore, the examiner finds it is reasonable to rejoin the two groups. Thus, the restriction is withdrawn and the inventions of Groups I and II are rejoined.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on September 20, 2024 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
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.
Claims 3, 7, 8, 11, 15, 16, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Rangnekar et al. (US 7,786,275 B2; Published: August 31, 2010) in view of GenBank Accession U05989.1 (Available: January 31, 2002), Burikhanov et al. (Cell. 138: 377-388; Published: July 24, 2009), Karrer et al. (WO 2009/058564 A2; Published: October 12, 2006), and Lo et al. (Protein Engineering. 11(6): 495-500; Published: June 1, 1998).
Rangnekar et al. teaches a fusion protein comprising a rat Par-4 fragment comprising residues 1-204, 137-221, 137-213, 137-198, or 137-195 of SEQ ID NO: 1; see issued claim 3. Rangnekar et al. teaches that the 59 amino acid core domain of Par-4 that constitutes a minimal region of Par-4 which is sufficient for apoptosis and which translocates into the nucleus in both cancer and normal or immortalized cells, but is selective in inducing apoptosis of the cancer cells, is 100% conserved in rat, mouse, and human Par-4. Rangnekar et al. teaches that the fusion protein may further comprise other proteins or antibodies; see column 3 line 47. The alignment below is of instant SEQ ID NO: 1 in the Qy line and Rangnekar et al. SEQ ID NO: 1 in the Db line. Instant SEQ ID NO: 1 corresponds to the Par-4 portion of instant SEQ ID NO: 6 and is 100% identical to residues 233-564 of instant SEQ ID NO: 6.
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Regarding claims 19 and 20, Rangnekar et al. teaches expressing the rat Par-4 polypeptide comprising nucleic acid encoding the Par-4 protein fragment in a vector and wherein a host cell comprises the vector; see claim 2.
Finally, regarding claims 7 and 15, Rangnekar et al. issued claim 4 and Example 2 teach using a pharmaceutical composition comprising residues 1-204, 137-221, 137-213, 137-198, or 137-195 of SEQ ID NO: 1.
While Rangnekar et al. teaches treating cancer with the fusion protein comprising Par-4 or a fragment thereof, it does not teach treating metastatic cancer.
Regarding claims 8 and 16, Burikhanov et al. teaches that Par-4 or its SAC domain (residues 137-195 of SEQ ID NO: 1) can function extracellularly to selectively promote apoptosis; see Abstract. In the final sentence of the Discussion, Burikhanov et al. suggests that the function of extracellular Par-4 and SAC broadens the therapeutic potential for treating primary and metastatic cancers.
While Rangnekar et al. teaches a fragment of the Par-4 protein, it does not teach a composition comprising SEQ ID NO: 6.
Regarding claims 3 and 11, and the translated Par-4 protein of GenBank Accession U05989.1 aligns 100% to SEQ ID NO: 1 and amino acids 235-566 of SEQ ID NO: 6. Additionally, regarding claim 18, GenBank Accession U05989.1 teaches the nucleic acid sequence encoding the Par-4 portion of the fusion protein, nucleotides 703-1701.
Additionally, while Rangnekar et al. teaches that the fusion protein comprising Par-4 may further comprise antibodies, it does not teach a fusion protein comprising a Fc fragment comprising residues 1-134 of SEQ ID NO: 6 nor that the order of the fusion protein from N- to C-terminus is Fc fragment, then Par-4.
Karrer et al. teaches a fusion protein comprising CLTA-4 and an Fc fragment, wherein the Fc fragment comprises residues 1-134 of instant SEQ ID NO: 6; see the alignment below where instant SEQ ID NO: 4, which is 100% identical to residues 1-134 of instant SEQ ID NO: 6, is in the Qy line and the Fc sequence of the fusion protein taught by Karrer et al., Karrer et al. SEQ ID NO: 186, is in the Db line.
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The fusion protein comprising the therapeutic protein and a Fc polypeptide as taught by Karrer et al. may be fused with a linker or directly; see claims 163 and 164.
Karrer et al. does not teach a fusion protein wherein the Fc fragment is located at the N-terminus.
Regarding the N- to C-terminus alignment in SEQ ID NO: 6, Lo et al. teaches that fusion proteins wherein the Fc fragment is located at the N-terminus could be recombinantly produced at a higher level than fusion proteins wherein the Fc fragment is located at the C-terminus; see the first paragraph of the Discussion. Further, Lo et al. teaches that the N-terminal Fc fragment had no impact on biological function of the fusion partner; see Biological Activities of Fc-X Proteins.
Given that Rangnekar et al. teaches that Par-4 can be fused to an antibody, which comprises an Fc region, and Karrer et al. teaches that fusing a Fc domain to a therapeutic improves the half-life of the therapeutic, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success combining a Par-4 polypeptide and a Fc polypeptide.
Given that Rangnekar et al. and Burikhanov et al. both teach that Par-4, specifically the conserved SAC domain, is necessary and sufficient to induce apoptosis and the Par-4 sequence taught by GenBank Accession U05989.1, which is identical amino acids 235-566 of instant SEQ ID NO: 6, comprises the SAC domain, it would have been obvious and one would have had a reasonable expectation of success to construct a Par-4 antibody (Fc) fusion protein as taught by Rangnekar et al. comprising the Par-4 sequence taught by GenBank Accession U05989.1 and the Fc region taught by Karrer et al.
Given that Karrer et al. teaches a fusion protein comprising the Fc fragment of instant SEQ ID NO: 4 has improved half-life (see pages 117 and 299), it would have been obvious to use the Fc fragment taught by Karrer et al. as the antibody portion of the fusion protein taught by Rangnekar et al. in order to extend of the half-life of the resulting Fc – Par-4 fusion protein. One would have had a reasonable expectation of success that using the Fc fragment taught by Karrer et al. would extend the half-life of the Fc – Par-4 fusion protein because Karrer et al. teaches that this Fc fragment resulted in extending the half-life of another fusion protein. Moreover, Karrer et al. teaches an Orencia dimer which comprises the Fc region of SEQ ID NO: 186 which is 100% identical to instant SEQ ID NO: 4. On pages 69-70 (the bridging sentence) Karrer et al. teaches that no disulfide bonds are formed between the two Fc regions. Thus, the function that the Fc does not dimerize naturally flows from the Fc region comprising SEQ ID NO: 4 which comprises the mutations at positions 5, 11, and 14 according to IMGT numbering.
Burikhanov et al. teaches that the SAC domain, the domain of Par-4 which is necessary and sufficient to induce apoptosis is a core domain. It would have been obvious to one of ordinary skill in the art that the Fc polypeptide could be fused to either the N- or C-terminal of Par-4. Further, one of ordinary skill in the art would have been motivated to order the fusion protein with an N-terminus Fc fragment in order to improve fusion protein yields as taught by Lo et al. Additionally, one would have had a reasonable expectation of success in ordering the fusion protein, N- to C- terminal, the Fc fragment then Par-4 because Lo et al. demonstrated that an N-terminal Fc fragment on a fusion protein improved yield and Lo et al. teaches that adding an Fc fragment can help to a protein can aid in the expression of difficult to express proteins, including hydrophobic proteins.
Given that Rangnekar et al. and Burikhanov et al. both teach that Par-4, specifically the conserved SAC domain, can selectively induce apoptosis in cancer cells, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to use the Par-4 containing fusion protein for the treatment of metastatic cancer; see Rangnekar et al. column 3 line 46, column 7 lines 65-67, and column 8 lines 1-2.
Finally, since the genetic code is widely known and it is a routine matter to convert back and forth between an amino acid sequence and the sequences of nucleic acid molecules which encode it, absent any secondary considerations, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to reverse translate from the amino acid sequence of SEQ ID NO: 6 as taught by Rangnekar et al. in view of GenBank Accession U05989.1, Burikhanov et al., Karrer et al., and Lo et al. to arrive at SEQ ID NO: 5.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Response to Arguments
Applicant’s amendments filed July 14, 2026 are acknowledged. Any rejection not repeated above is resolved by amendment.
The rejection of claim 18 under 35 U.S.C. 103 further in view of Zhan et al. (US 10,772,940 B1) is overcome. Applicant claims common ownership and the reference is an exception under 35 U.S.C. 102 (b)(2)(C). Zhan et al. is not prior art under 35 U.S.C. 102(a)(1) as it is not published before the effective filing date.
The nonstatutory double patenting rejection over the issued claims of US 7,786,275 B2 is overcome by amendment. The issued claims do not teach either the Par-4 nor the Fc portion of instant SEQ ID NOs: 5 or 6.
On pages 5-6, Applicant argues that there is no motivation to select this Fc region nor combine it with Par-4 and reasonable expect the retention of Par-4 apoptotic activity. At to the specific Fc region, Karrer et al. teaches improved half life and using the mutant IgG1 what does not dimerize and dhas reduced immunogenicity and effector function; see page 117. Combining an Fc region is with Par-4 if taught by Rangnekar et al.; see the rejection above. Burikhanov et al. teaches that the SAC domain of Par-4 (residues 137-195) is necessary and sufficient to induce apoptosis. This SAC domain is central within the Par-4 portion of SEQ ID NO: 6 and, as stated above, one would have conclude that the Fc region could be added to either the N- or C-terminus without disrupting the apoptotic function. Applicant has provided no evidence to the contrary.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Sarkar et al. (Frontiers in Plant Science. 6:822; Published: October 7, 2015) teaches a fusion protein comprising the SAC domain of rat Par-4 and GFP. The rat Par-4 was obtained from GenBank accession U05989 which comprises a sequence which aligns with SEQ ID NO: 5 and translates to a sequence found in SEQ ID NOs: 1 and 7. Chen et al. (Cell Death and Differentiation. 21: 1535-1545; Published: July 4, 2014) teaches that Par-4 has a short half-life; see page 2 right column.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 8:30am - 5:00pm MT.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
