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 .
DETAILED ACTION
The amendment filed May 7, 2026 in response to the Office Action of November 14, 2025 is acknowledged and has been entered.
Claims 1, 35, 36, 40, and 46 have been amended.
Claims 2-11 have been cancelled.
Claim 51 has been added.
Claims 1, 12-14, 35-37, 39, 40, 46, and 51 are pending.
Claims 35-37, 39 and 46 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1, 12-14, 40 and 51 are currently under consideration as drawn to the elected invention.
It is noted that prior arts does not teach or suggest the heterodimer of claim 1 comprising the specific sequences as recited by claim 51.
In view of the claim 40 amendment, the 112(b) rejection set forth in the previous Office Action of November 14, 2025 is hereby withdrawn.
In view of the claim 1 amendment and applicant’s arguments, the 112(a) rejection set forth in the previous Office Action of November 14, 2025 is hereby withdrawn.
MAINTAINED/MODIFIED REJECTIONS
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 (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.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 12-14 and 40 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Schreiber (Schreiber et al., US 2019/0151413 A1, Publication Date: 05/23/2019, cited as No. 17 reference in IDS of 03/16/2022), in view of Sturgill (Sturgill et al., AJHO. 2017; 13(11): 4-15, Publication Year: 2017) and Ha (Ha et al., Frontiers in Immunology, vol. 7, article 394, Publication Date: 10/06/2016).
Schreiber teaches a fusion protein comprising: (a) a first extracellular domain of type I transmembrane protein at the N-terminus, (b) a second extracellular domain of a type II transmembrane protein at the C-terminus, (c) a linker ([0005], [0012], and Fig. 1).
Schreiber teaches that in some embodiments, the fusion protein comprises the extracellular domain of PD-1 and is paired with ab immune stimulatory agent such as: PD1/4-1BBL, PD-1/OX-40L, … ([0053]). Schreiber teaches making various fusion proteins including PD-1-Fc-41BBL, … (see Fig. 17A, Example 5).
Schreiber teaches that in various embodiments, the linker comprises an Fc domain of an antibody, such as a hinge-CH2-Ch3 Fc domain derived from IgG4 or IgG1 ([0097]). Schreiber teaches that there are dimeric formation for the fusion protein ([0205]). As evidenced by the original claim 4, Fc domain is a dimerizing moiety.
Schreiber teaches that the Fc domain linker may contain one or more mutations ([0098]-[0101]).
Schreiber teaches that the linker may function to improve the folding and/or stability, or improve the pharmacokinetics ([0105]).
Schreiber teaches that the fusion proteins can be co-administered ([0141]).
Schreiber teaches the method of making PD-1-Fc-OX40L protein (Example 1). Binding assays showed that PD-1-Fc-OX40L can bind OX40 and PD-L1. Thus, the amino acid sequence of type I membrane protein or type II membrane protein is capable of binding a natural ligand ([0202]).
Schreiber teaches that in vivo administration of PD-1-Fc-OX40L led to tumor regression in the B16.F10-ova tumor model ([0204]). Schreiber teaches that the PD-1-Fc-4-1BBL also led to reduced tumor size in treated animals ([0208]).
Schreiber teaches that an extracellular domain (ECD) of PD-1 is used in the fusion protein ([0069], [0070]). The exemplary ECD of PD-1 (in SED ID NO: 2 of Schreiber) comprises the instant SEQ ID NO: 5:
US-15-281-196A-2
Query Match 100.0%; Score 908; Length 534;
Best Local Similarity 100.0%;
Matches 167; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTS 60
Qy 61 ESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGT 120
Qy 121 YLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQ 167
|||||||||||||||||||||||||||||||||||||||||||||||
Db 121 YLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQ 167
Schreiber teaches that the amino acid sequence of 4-1BBL: SEQ ID NO: 58 (see Table on page 124, [0257]). As shown below, SEQ ID NO: 58 comprises the instant SEQ ID NO: 49:
Query Match 100.0%; Score 1041; Length 205;
Best Local Similarity 100.0%;
Matches 205; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSW 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSW 60
Qy 61 YSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQP 120
Qy 121 LRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLT 180
Qy 181 QGATVLGLFRVTPEIPAGLPSPRSE 205
|||||||||||||||||||||||||
Db 181 QGATVLGLFRVTPEIPAGLPSPRSE 205
Thus, Schreiber teaches the specific sequences recited by amended claim 1.
Schreiber teaches that PD-1-Fc-OX40L resulted in greater tumor regression that the OX40 agonist and PD-L1 blocking antibody in CT26 colorectal cancer model (Fig. 11L and [0212]).
Schreiber teaches treating cancers with the pharmaceutical composition comprising the fusion protein (claim 71).
Schreiber’s teachings are described above. However, Schreiber does not explicitly teach a heterodimer comprising the recited components.
Sturgill teaches that the tumor microenvironment is often immunosuppressive and lacks the appropriate signals necessary for stimulating effective anti-tumor T-cell responses (Abstract).
Sturgill teaches that T cells express both activating (such as 4-1BB and OX40) and inhibitory receptors (such as PD-1). These receptors can be targeted in order to increase T-cell activation (see Figure on page 6).
Sturgill teaches that 4-1BB agonist in combination with OX40 agonist and PD-1 inhibitor combination has been tested in clinical settings (page 7, col. 2, para. 2).
Ha teaches that use heterodimeric Fc as alternative scaffold of wild-type Fc for naturally heterodimeric proteins, to create Fc-fusion proteins with novel therapeutic modality (Abstract).
Ha teaches methods making heterodimeric Fc variant: “Knobs-into-Hole (KiH)” Fc technology (page 3, col. 1, para. 1; and Fig. 2B).
Ha teaches that heterodimeric Fc technology is now emerging as a promising scaffold for the generation of Fc-fused protein. The heterodimeric Fc capability will facilitate the development of the next generation of Fc-fused proteins that maintain full function of the fusion partner, while retaining the Fc-mediated extended half-life and immune effector functions (the bridging paragraph of cols. 1-2 on page 13).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make various Fc fusion proteins such as PD-1-Fc-OX40L, and PD-1-Fc-4-1BBL (e.g. the sequences listed in Table on page 124) for treating cancers as taught by Schreiber, and to combine the Fc fusion proteins e.g. PD-1-Fc-OX40L+ PD-1-Fc-4-1BBL, because Schreiber teaches that both fusion proteins are effective in reducing B16.F10-ova tumor. Schreiber also teaches that the fusion proteins can be used in combination. Sturgill teaches that targeting PD-1, OX40 and 4-1BBL can increase T cell activation. One of ordinary skill in the art would further modify the fusion protein by using a heterodimeric Fc as alternative scaffold to bring the two fusion protein together, because Ha teaches that heterodimeric Fc (such as KiH) is widely used in the art, can create Fc-fusion proteins with novel therapeutic modality, and the heterodimeric Fc format can maintain full function of the fusion partner, while retaining the Fc-mediated extended half-life and immune effector functions. Based on the teachings of the references, one of ordinary skill in the art would have had a reasonable expectation that the heterodimer of PD-1-Fc-OX40L and PD-1-Fc-4-1BBL would have enhanced therapeutic activity to cancers (such as ovary cancer) because both monomers have anti-tumor activity in B16.F10-ova tumor model. The motivation would be to develop a more potent therapeutic composition for treating cancers.
Regarding claims 12 and 13, a heterodimer comprising PD-1-Fc-OX40L and PD-1-Fc-4-1BBL would read on the claims, because both monomers comprise one amino acid sequence of at least one type I membrane protein and one amino acid sequence of at least one type II membrane protein.
Regarding claim 14, the monomer PD-1-Fc-OX40L would read on the limitation “a first monomer comprising at least one of said at least two amino acid sequences of said at least two type I membrane proteins and said at least one amino acid sequence of said at least one type II membrane protein”; and the monomer PD-1-Fc-4-1BBL would read on the limitation: “a second monomer comprising at least one of said at least two amino acid sequences of said at least two type I membrane proteins”.
Regarding claim 40, the intended use does not change the structure of the heterodimer of claim 1.
Response to Arguments
For the rejection of claims 1, 12-14, and 40 under 35 U.S.C. 103, Applicant mainly argues: “None of Schreiber, Sturgill, Ha, and Yang teach or suggest the claimed SEQ ID NOs: for the at least one type I membrane protein and the at least one type II membrane protein”.
Applicant’s arguments have been considered, but have not been found persuasive. As set forth above, contrary to Applicant’s argument, Schreiber teaches at least SEQ ID NO: 5 (ECD of PD1 in SEQ ID NO: 2 of Schreiber) and SEQ ID NO: 49 (exemplary 4-1BBL sequence of SEQ ID NO: 49 of Schreiber). Accordingly, the combined references teach the amended claims.
NEW REJECTION
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 12 recites the limitation "said at least one amino acid sequence" in line 2 and line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim 13 recites the limitation "said at least one amino acid sequence" in line 2 and lines 3-4. There is insufficient antecedent basis for this limitation in the claim.
Claim 14 recites the limitation "said at least one amino acid sequence" in lines 1- 2, and line 5. There is insufficient antecedent basis for this limitation in the claim.
Conclusion
Claims 1, 12-14, and 40 are rejected.
Claim 51 is objected because they are dependent on the rejected claims directly or indirectly. However, claim 51 would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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