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 (i.e., claims 1-4, 6, 9, and 15-17 drawn to a heterodimer) in the reply filed on March 19, 2026, is acknowledged. Additionally, Applicant’s election without traverse of Species A (i.e., a heterodimer comprising a TIGIT polypeptide attached to IgG1 as a dimerizing moiety as a first monomer, and a PD1 polypeptide attached to IgG4 as a dimerizing moiety as a second monomer) in the reply filed on March 19, 2026, is acknowledged. Since Applicant’s election Group I, election of a single and specific disease (i.e., Species B) is moot.
Status of Claims
Claims 1-30 were originally filed on July 13, 2023.
The amendment received on July 13, 2023, canceled claims 5, 7-8, 10-14, 23, and 28; and amended claims 6, 9, 15-20, 22, 24-27, and 29.
Claims 1-4, 6, 9, 15-22, 24-27, and 29-30 are currently pending and claims 1-4, 9, 15, and 17 are under consideration as claims 18-22, 24-27, and 29-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, and claims 6 and 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 19, 2026.
Priority
The present application claims status as a 371 (National Stage) of PCT/IL2022/050055 filed January 13, 2021, and claims priority under 119(e) to U.S. Provisional Application Nos. 63/136,687 filed on January 13, 2021, and 63/139,331 filed on January 20, 2021.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on September 5, 2023; September 13, 2023; September 19, 2023; October 8, 2023; October 15, 2023; October 22, 2023; October 29, 2023; November 22, 2023; November 27, 2023; December 5, 2023; December 12, 2023; December 26, 2023; December 31, 2023; January 7, 2024; January 22, 2024; January 28, 2024; February 4, 2024; February 25, 2024; March 31, 2024; April 30, 2024; June 16, 2024; July 2, 2024; July 21, 2024; September 22, 2024; October 6, 2024; October 13, 2024; October 20, 2024; November 3, 2024; December 26, 2024; January 1, 2025; January 13, 2025; March 19, 2026, are being considered by the examiner.
Please note that the following references have been crossed out and not considered because an English language abstract, translation or statement of relevance has not been provided pursuant to 37 CFR 1.98: NPL1, i.e., Appeal Against Decision of Refusal, 11/19/24 from Japan, cited in the IDS received on 12/26/24; and NPL2, i.e., Notice of Reason(s) for Rejection, 11/28/23 from Japan, cited in the IDS received on 12/12/23.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 9, 15, and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. Please note that the rejection is limited to Applicant’s species election indicated supra.
Independent claim 1 is directed to a “heterodimer comprising two polypeptides selected from SIRP-alpha, PD1, TIGIT, LILRB2 and SIGLEC10” where the heterodimer does not comprise an amino acid sequence of a type II membrane protein. One of the polypeptides is a TIGIT polypeptide, and the second polypeptide is a PD1 polypeptide. It is noted that the instant specification defines a “PD1 polypeptide” as encompassing functional homologues which exhibit the desired activity (See instant, pg. 15, 8th paragraph). Such homologues can be at least 70% identical or homologous to SEQ ID NOs: 37, 41-43, or any other PD1 amino acid sequence (See instant, pg. 15, 8th paragraph), but is not required. Moreover, the instant specification teaches that the homolog can refer to an ortholog, a deletion, insertion or substitution variant including an amino acid substitution (See instant, pg. 15, last paragraph). As such, the scope of the elected “PD1 polypeptide” encompasses homologues where such homologues include deletions, insertions, and/or substitutions. These PD1 homologues are to exhibit the desired activity, i.e., functional homologues, where claim 1 recites that PD1 is capable of binding a natural binding pair thereof, e.g., PD-L1 or PD-L2. Thus, there is no core structure or sequence of a PD1 polypeptide necessary to exhibit the function of binding a natural binding pair thereof. Similarly, the instant specification defines a TIGIT polypeptide as a polypeptide encoded by the TIGIT gene (Gene ID 201633), and encompasses functional homologues, which exhibit the desired activity (See instant, pg. 22, 1st and last paragraph). The TIGIT polypeptide can comprise an extracellular domain of TIGIT or a functional homolog, e.g., fragment, thereof (See instant, pg. 22, 6th paragraph). Such homologues can be at least 70% identical or homologous to SEQ ID NOs: 106-107, 113 or 115 or any other TIGIT amino acid sequence (See instant, pg. 22, last paragraph), but is not required. The TIGIT polypeptide can also comprise conservative and non-conservative amino acid substitutions (See instant, pg. 23, 2nd paragraph). As such, the scope of the elected “TIGIT polypeptide” encompasses homologues, fragments, and variants. These TIGIT polypeptides are to exhibit the desired activity, i.e., functional homologues, where claim 1 recites that TIGIT is capable of binding a natural binding pair thereof, e.g., CD155 (PVR) (See instant, pg. 22, 4th paragraph). Thus, there is no core structure or sequence of a TIGIT polypeptide necessary to exhibit the function of binding a natural binding pair thereof. Therefore, the claimed invention encompasses a vast array of heterodimers without a core structure or sequence necessary for each of the two polypeptides is capable of binding a natural binding pair thereof.
Furthermore, dependent claims 2-3 are directed to where the heterodimer further comprises a dimerizing moiety attached to the two polypeptides such as an Fc domain of an antibody or fragment thereof. The instant specification defines a “dimerizing moiety” as a moiety capable of attaching two different monomers to form a heterodimer (See instant, pg. 32, 2nd paragraph). The dimerizing moiety includes chemical and proteinaceous moieties (See instant, pg. 32, 2nd paragraph). As such, the dimerizing moiety encompasses any chemical moiety, e.g., crosslinkers, organic polymers, synthetic polymers, or a small molecule, and any proteinaceous moiety, e.g., affinity polypeptide pairs and Fc domain of an antibody (See instant, pg. 33, 3rd to 4th paragraphs; pg. 34, 9th to last paragraph). Moreover, the instant specification teaches that a Fc domain as a dimerizing moiety can comprise conservative and non-conservative amino acid substitutions (See instant, pg. 35, 6th to 8th paragraphs). As such, IgG1 and IgG4 as the elected dimerizing moieties of claims 2-3 encompass any variants and fragments thereof. The elected dimerizing moieties must also contain a modification where such modification results in the elected dimerizing moieties exhibiting the function of alteration of the binding to a Fc receptor, reduction of an immune activating function thereof and/or half-life improvement of the heterodimer. Therefore, the claimed invention encompasses a vast array of dimerizing moieties without a core structure or sequence necessary for the dimerizing moieties to alter binding to a Fc receptor, reduce an immune activating function and/or improve the half-life of the heterodimer. Thus, the claimed heterodimer encompasses an enormous array of components without a core structure or sequence necessary for the heterodimer to exhibit the claimed functions.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art for PD1 polypeptides, Maute et al. identified specific residues within a specific portion of the natural human PD1 protein, i.e., the PD1 ectodomain, that can improve a PD1 polypeptide’s binding affinity to PD-L1 (See Maute et al., Proc. Natl. Acad. Sci. USA 112:E6506-E6514 (2015) at abstract; pg. E6507, col. 2, last paragraph; Figure 1C) (cited in the IDS received on 9/5/23), which is a natural binding pair with PD1. However, Maute et al. teaches that although the resulting clones showed 400-500 fold increase in affinity for hPD-L1, the clones also exhibited poor biochemical behavior, with decreased expression yield and a tendency toward aggregation (See Maute, pg. E6507, col. 2, last paragraph). Inspection of the variants as depicted in Figure 1C revealed an average of 16 mutations per clone, with several of the randomized positions converging on a small set of mutations (e.g., V39, N41) (See Maute, pg. E6507, col. 2, last paragraph). Other positions appeared to either diverge (e.g., S48, D52) or have a strict preference for the original wild-type residue (e.g., P105, E111) (See Maute, pg. E6507, col. 2, last paragraph to pg. E6508, col. 1, 1st paragraph). Maute et al. interpreted these results as that the first-generation variants likely contained a mixture of beneficial mutations, non-functional passenger mutations, and deleterious mutations (See Maute, pg. E6508, col. 1, 1st paragraph). As such, Maute et al. created a second-generation library focusing on mutations that impart enhanced affinity as depicted in supplemental material, Figure S2 (See Maute, pg. E6508, col. 1, 2nd paragraph; Supplemental Material, Figure S2). The second-generation library demonstrated a consensus sequence of 10 amino acid substitutions comprising 8 contact residues and 2 core residues as depicted in Figure 1C (See Maute, pg. E6508, col. 1, 2nd paragraph). Although Maute et al. demonstrates a core consensus sequence containing 10 residues at positions 39-43, 45, 49, 53, 97, 100 and 107 that exhibit binding affinity to PD-L1, the specific core consensus sequence is representative of a smaller subgenus of PD1 polypeptide sequences, i.e., a sequence requiring the full length PD1 sequence with specific substitutions at specific positions. As such, the teachings of Maute et al. cannot constitute a representative number of PD1 polypeptides given the breadth of the claimed PD1 polypeptides as discussed supra or a core sequence because the data provided by Maute et al. cannot be extrapolated to apply to the full scope of the claimed PD1 polypeptides.
With regard to the state of the art for TIGIT polypeptides, Sun et al. identified several critical epitopic TIGIT residues (See Sun et al., Structure 32:550-561 (2024) at highlights section). Sun et al. teaches that TIGIT have various ligands including PVR (CD155, NecI5, or Tage4), nectin-2 (PVRL2 or CD112), nectin-3 (PVRL3 or CD113) and nectin-4 (PVRL4) (See Sun, pg. 550, col. 1, last paragraph). In determining the crystal structure of different antibodies in complex with TIGIT, Sun et al. found that the epitope of TIGIT contains residues Q56, E60, D63, Q64, L65, I68, N70, L73, G74, W75, J76, S78, P79, S80 and K82 (See Sun, pg. 552, col. 2, last paragraph). Sun et al. also found that 10 residues of TIGIT (epitope) are involved in paratope-epitope formation; namely, Q56, N58, E60, H76, I77, S78, P79, S80, K82 and H111 (See Sun, pg. 553, col. 1, 2nd paragraph). Moreover, Sun et al. introduced several mutations in a recombinant TIGIT to determine if the mutations affected binding affinity for the antibodies tested (See Sun, pg. 553, col. 2, last paragraph). A TIGIT polypeptide with a L73A mutation has a similar association rate but a slightly faster disassociation rate to wild type resulting in an approximately 7-fold reduction in binding affinity whereas a H76A mutation nearly abolished antibody binding suggesting that this residue is critical for the interaction (See Sun, pg. 554, col. 1, 2nd paragraph). Figure 5 depicts the TIGIT mutations examined along with associated binding affinity to the antibodies (See Sun, pg. 554, col. 1, 2nd paragraph to pg. 555, col. 2, 1st paragraph; Figure 5; Table 1). As such, Sun et al. demonstrates that a single mutation of one of these residues can affect the function of the TIGIT polypeptide. However, Sun et al. also found that single mutations of nearly residues, i.e., T55A, D83A, V85A, P87A, and I109A, around the epitope had no effect on its binding (See Sun, pg. 555, col. 1, 1st paragraph). Although Sun et al. demonstrates critical residues of TIGIT that are necessary for TIGIT to exhibit binding affinity to two different antibodies, the specific core consensus sequence is representative of a smaller subgenus of TIGIT polypeptide sequences, i.e., a sequence requiring the full length TIGIT sequence with specific single substitutions at specific positions, where such a subgenus of TIGIT polypeptide sequences would form the proper structure to complex with a natural binding pair. As such, the teachings of Sun et al. cannot constitute a representative number of TIGIT polypeptides given the breadth of the claimed TIGIT polypeptides as discussed supra or a core sequence because the data provided by Sun et al. cannot be extrapolated to apply to the full scope of the claimed TIGIT polypeptides, and demonstrates that even a single mutation can greatly impact the function of the TIGIT polypeptide.
With regard to the state of the art for dimerizing moieties, Delidakis et al. teaches that modifications in the Fc that impact Fc receptor engagement have been shown to drastically affect the efficacy of antibody therapeutics (See Delidakis et al., Annu. Rev. Biomed. Eng. 24:249-274 (2022) at pg. 3, last paragraph). Efforts to alter either the composition of the glycan or the protein backbone of the Fc have been employed to create second-generation therapeutics with properties such as increased efficacy, lower toxicity, extended half-life for easier administration and lower manufacturing costs (See Delidakis, pg. 3, last paragraph). Examples of antibodies having modified Fc domains to modulate effector FcR functions are listed in Table 1 including chimeric IgG1 or IgG2/4 antibodies with one to six specific substitutions, e.g., IgG1 with five specific mutations: L235V, F243L, R292P, Y300L, and P396L; IgG1 with six specific mutations: G236A, S239D, A330L, I332E+ M428L, and N434S; and humanized IgG1 with two specific mutations: S267E and L328F (See Delidakis, pg. 3, last paragraph; Table 1). Moreover, Delidakis et al. teaches that the contact subsites of all IgG isotypes to the six members of the FcγR family are conserved with the largest contribution to receptor binding affinity arising from the lower hinge (See Delidakis, pg. 11, last paragraph). FcγR binding to IgG is asymmetric with respect to the two heavy chain polypeptides, A and B (See Delidakis, pg. 11, last paragraph). Chain B interacts with FcγRs primarily by forming salt bridges and via hydrogen bonding with residues in the B/C and C’/E loops of CH2 in addition to van der Waals interactions with the lower hinge (See Delidakis, pg. 11, last paragraph). Chain A forms a tight interaction between Pro329 in the F/G loop of the Fc and two conserved Trp residues found in all FcγRs termed a proline sandwich (See Delidakis, pg. 11, last paragraph). The high affinity of FcγRI for IgG1 is attributed to the Leu235 residue of IgG1 (See Delidakis, pg. 11, last paragraph). Furthermore, Delidakis et al. teaches that a lower-hinge mutation (G236A) selectively increases the FcγRIIa affinity over FcγRIIb translating to better macrophage phagocytosis, and discusses a study that isolated more than 400 possible single Fc mutations that enhanced FcγRIIIa and decreased FcγRIIIb affinity (See Delidakis, pg. 14, 1st paragraph). This study then combined mutations on both the extended FcγR binding site (F243L, R292P, and Y300L) and the CH2:CH3 interface (P396L) to achieve a tenfold increase in FcγRIIIa affinity (See Delidakis, pg. 14, 1st paragraph). An additional mutant, termed LALA, containing the double mutant (L234A/L235A) has been used to disrupt the conserved FcγR binding site (See Delidakis, pg. 15, 2nd paragraph). Plus, the introduction of a K322A mutation in the lower CH2 domain greatly reduces binding to C1q and CDC while only slightly affecting FcγR binding (See Delidakis, pg. 16, 2nd paragraph).
Although Delidakis et al. demonstrates a number of mutant Fc domains that exhibit the claimed functions, these species are representative of a smaller subgenus of Fc domain sequences, i.e., a sequence requiring the full length Fc domain sequence with specific single substitutions at specific positions, where such a subgenus of Fc domain sequences would form the proper structure to exhibit the claimed functions. As such, the teachings of Delidakis et al. cannot constitute a representative number of Fc domains, let alone dimerizing moieties, given the breadth of the claimed dimerizing moieties as discussed supra or a core structure/sequence because the data provided by Delidakis et al. cannot be extrapolated to apply to the full scope of the claimed dimerizing moieties, and demonstrates that even a single Fc domain mutation can greatly impact the function of the Fc domain. Thus, the claims are directed to polypeptides and dimerizing moieties with certain functions but no correlated structure associated with those functions. Without such structure, the specification does not convey possession of the breadth of the claimed genera.
Alternatively, the written description requirement may be met by provided a representative number of species of the genus. In this, the specification teaches several specific species of PD1 polypeptides, TIGIT polypeptides, and dimerizing moieties meeting the claimed limitations. With respect to PD1 polypeptides, the instant specification teaches PD1 amino acid sequences of SEQ ID NOs: 37, 39, 41-43, 45, 47, 49, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, and 81 (See instant, pg. 18, 2nd paragraph). Plus, the specification teaches that the PD1 polypeptide comprises 100-288 amino acids, 100-200 amino acids, etc. (See instant, pg. 18, 1st paragraph) without identifying which amino acids are included. The specification also identifies many specific residues and specific substitutions such as V39H or V39R, L40V or L40I, etc. (See instant, pg. 16, 3rd to last paragraph). Although the specification provides many specific PD1 polypeptide amino acid sequences and more general teachings of percent identity/homology and positions that can be substituted, the specific PD1 polypeptide amino acid sequences are representative of a smaller subgenus of polypeptide sequences that are fragments of a specific portion of the full length PD1 protein, i.e., SEQ ID NO: 37, and have a high sequence identity to that PD1 domain. For example, SEQ ID NOs: 39, 43, 57, 59, 61, and 63 may have a single substitution C93S and are range from about residue 20 to about residue 170 of natural SEQ ID NO: 37. As such, the specific species taught in the specification do not constitute a representative number of PD1 polypeptides given the breadth of the claimed PD1 polypeptides as discussed supra because the specific species do not identify a core structure or sequence necessary for each PD1 polypeptide to exhibit the function of binding to a natural binding pair thereof.
With respect to TIGIT polypeptides, the specification teaches that the TIGIT polypeptide comprises SEQ ID NOs: 106-107, 109, 111, 113, or 115 (See instant, pg. 22, 2nd and 7th paragraphs; pg. 23, 6th paragraph). Plus, the specification teaches that the TIGIT polypeptide comprises 100-244 amino acids, 100-200 amino acids, etc. (See instant, pg. 23, 10th paragraph) without identifying which amino acids are included. Although the specification provides a handful of specific TIGIT polypeptide amino acid sequences and more general teachings of percent identity/homology, the specific TIGIT polypeptide amino acid sequences are representative of a smaller subgenus of polypeptide sequences that are fragments of a specific portion of the full length TIGIT protein, i.e., SEQ ID NO: 106, and have a high sequence identity to that PD1 domain. For example, SEQ ID NOs: 107, 109, 111, 113 or 115 may have a single substitution C69S or double substitution of I42A and C69S, and are range from about residue 20 to about residue 135 of natural SEQ ID NO: 106. As such, the specific species taught in the specification do not constitute a representative number of TIGIT polypeptides given the breadth of the claimed TIGIT polypeptides as discussed supra because the specific species do not identify a core structure or sequence necessary for each TIGIT polypeptide to exhibit the function of binding to a natural binding pair thereof.
With respect to dimerizing moieties, the specification teaches the dimerizing moiety include chemical/non-proteinaceous and proteinaceous moieties (See instant, pg. 32, 2nd paragraph). Non-proteinaceous moieties include crosslinkers, organic polymers, synthetic polymers, and small molecules, etc., such as NHS-esters, carboiimides, maleimide groups, sulfo-SANPAH, SMPH, PDPH, affinity pair polypeptides, e.g., HA, anti-HA, His, biotin, avidin and streptavidin, and an antibody Fc domain or fragment thereof (See instant, pg. 32, 3rd paragraph; pg. 33, 3rd paragraph to pg. 34, 1st, 9th to last paragraph). Specific Fc domain amino acid sequences include SEQ ID NO: 134-136, 157-159, and 163-164 (i.e., an IgG4 domain) and SEQ ID NOs: 27-28, 51-52, 136-137, 152, and 161-162 (i.e., IgG1 domain) (See instant, pg. 35, 1st to 2nd paragraph). Moreover, the specification teaches that the Fc domain can comprise conservative and nonconservative substitutions (See instant, pg. 35, 6th paragraph) without identifying a core structure or sequence necessary for the Fc domain sequence to exhibit the functions recited in instant claim 4. The specification also identifies a handful of specific residues and specific substitutions such as S228P, L235E, T366W, Y349C, T366S, L368A, Y407V and/or E356C (See instant, pg. 36, 3rd to last paragraph). Although the specification provides species of non-proteinaceous dimerizing moieties, these species are representative of a smaller subgenus of non-proteinaceous dimerizing moieties, in particular, heterobifunctional crosslinkers. Similarly, although the specification provides species of proteinaceous dimerizing moieties and more general teachings of percent identity/homology, the specific Fc domain polypeptide amino acid sequences are representative of a smaller subgenus of polypeptide sequences that have a high sequence identity to that the natural IgG1 or IgG4 domain. As such, the specific species taught in the specification do not constitute a representative number of dimerizing moieties given the breadth of the claimed dimerizing moieties as discussed supra, and especially, Fc domain amino acid sequences as dimerizing moieties because the specific species do not identify a core structure or sequence necessary for each Fc domain to exhibit the function of binding to an Fc receptor, reduce an immune activating function, and/or improve half-life of the heterodimer. Thus, the teachings in the specification are not sufficient for the skilled artisan to envisage which PD1 polypeptides, TIGIT polypeptides, and/or dimerizing moieties are encompassed that preserve the claimed functions.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, what is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides which preserve the required function, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, claims 1-4, 9, 15, and 17 do not meet the written description requirement.
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.
Claim 4 is 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 4 recites the limitation "the fusion" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Please note that the Examiner is interpreting the scope of claim 4 such that it is referring to “said heterodimer” in order to advance prosecution.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 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 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1-4, 9, 15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Schreiber et al. US Publication No. 2020/0216505 A1 published on July 9, 2020.
For claims 1-3, 9, and 15, ‘505 teaches a heterodimeric protein comprising a complex of two polypeptide chains, an alpha chain and a beta chain (note: polypeptide chain constitutes a monomer as elected) where the alpha chain and the beta chain each independently comprise (a) a first domain comprising a butyrophilin family protein or fragment thereof; (b) a second domain comprising a targeting domain, the targeting domain being selected from (i) an antibody, antibody-like molecule, or antigen binding fragment thereof, and (ii) an extracellular domain; and (c) a linker that adjoins the first and second domain (See ‘505, [0018]-[0019], [0094], [0121]-[0123], [0128]-[0129]). ‘505 teaches that the targeting domain comprises a portion of the extracellular domain of LAG-3, PD-1, TIGIT, CD19 or PSMA (See ‘505, [0075], [0094], [0121], [0128], [0135]-[0136], [0138]-[0139]). The alpha and beta chains self-associate to form the heterodimer in some embodiments (See ‘505, [0020]). Thus, the teachings of ‘505 satisfy the claim limitations with respect to a heterodimer comprising two polypeptides where each of the polypeptides is a monomer in the heterodimer as recited in instant claims 1 and 15.
With respect to a PD-1 polypeptide, the instant specification defines a “PD1 polypeptide” as encompassing functional homologues which exhibit the desired activity (See instant, pg. 15, 8th paragraph). Moreover, the instant specification teaches that the homolog can refer to an ortholog, a deletion, insertion or substitution variant including an amino acid substitution (See instant, pg. 15, last paragraph) thereby encompassing a PD-1 fragment (i.e., deletions). Thus, the targeting domain comprising a portion of the extracellular domain of PD-1 constitutes the instant PD-1 polypeptide, i.e., a PD-1 homolog, as recited in instant claims 1 and 9.
With respect to the TIGIT polypeptide, the instant specification defines a TIGIT polypeptide as a polypeptide encoded by the TIGIT gene (Gene ID 201633), and encompasses functional homologues, which exhibit the desired activity (See instant, pg. 22, 1st and last paragraph). The TIGIT polypeptide can comprise an extracellular domain of TIGIT or a functional homolog, e.g., fragment, thereof (See instant, pg. 22, 6th paragraph). Thus, the targeting domain comprising a portion of the extracellular domain of TIGIT constitutes the instant TIGIT polypeptide, i.e., a TIGIT homolog, as recited in instant claims 1 and 9. A specific example of a polypeptide chain, either the alpha or beta chain is a TIGIT-Fc-vBTNL3/8 heterodimer (See ‘505, [0054]). As such, this specific example can constitute the alpha or beta chain in ‘505’s complex in a heterodimeric protein where the chain comprises one of the two polypeptides as recited in instant claims 1 and 9, i.e., TIGIT, and a Fc domain as a linker thereby constituting the instant dimerizing moiety as recited in instant claims 2-3.
With respect to the dimerizing moiety, the instant specification defines a “dimerizing moiety” as a moiety capable of attaching two different monomers to form a heterodimer (See instant, pg. 32, 2nd paragraph). It is further noted that the scope of claim 2 does not require that a single dimerizing moiety is attached to both polypeptides. Rather, the broadest reasonable interpretation of claim 2 encompasses where a dimerizing moiety is attached to each of the two polypeptides. Such an interpretation is supported by Applicant’s species election where each polypeptide is a monomer that is attached to individual dimerizing moieties.
As discussed supra, ‘505’s complex in a heterodimeric protein comprises a linker that links the first domain, i.e., a butyrophilin family protein, and the second domain, i.e., targeting domain, together. ‘505 also teaches that the linker facilitates heterodimerization (See ‘505, [0094]). As such, ‘505’s linker constitutes the instant dimerizing moiety as recited in instant claim 2. Plus, ‘505 teaches that the linker can be a hinge region of an antibody, e.g., of IgG including IgG1 and IgG4 (See ‘505, [0109]) thereby constituting a Fc domain fragment as recited in instant claim 3. Alternatively, the linker as a stabilizing domain comprises a Fc domain of an antibody such as IgG including subclasses such as IgG1 and IgG4 (See ‘505, [0111]). Thus, the teachings of ‘505 satisfy the claim limitations with respect to where the heterodimer comprises a dimerizing moiety attached to the two polypeptides as recited in instant claim 2, and with respect to where the dimerizing moiety is an Fc domain of an antibody or a fragment thereof as recited in instant claim 3.
With respect to where each of the two polypeptides is capable of binding a natural binding pair thereof, as discussed supra, ‘505 teaches that the two polypeptides can be TIGIT and PD1. ‘505 also teaches that when the second domain comprises a portion of the extracellular domain of LAG-3, PD1, or TIGIT and which is capable of binding its receptor/ligand on the surface of a cancer cell (See ‘505, [0135]). Thus, the teachings of ‘505 satisfy the claim limitation with respect to where each of the two polypeptides is capable of binding a natural binding pair thereof as recited in instant claim 1.
Additionally, even if ‘505 did not expressly teach that the TIGIT and PD1 polypeptides are capable of binding a naturally binding pair thereof, since ‘505 teaches a TIGIT and PD1 polypeptide, the functional property of each (i.e., capable of binding a natural binding pair) of the TIGIT and PD1 polypeptides as claimed and the known TIGIT and PD1 polypeptides would necessarily read upon the same. The discovery of a previously unappreciated property of a prior art composition, or a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of new functional property of each (i.e., capable of binding a natural binding pair) which would necessarily read upon the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 4333 (CCPA 1977).
With respect to where the heterodimer does not comprise an amino acid sequence of a type II membrane protein capable of binding a natural binding pair thereof, it is noted that ‘505 does not require that the heterodimer protein contain an amino acid sequence of a type II membrane protein. Thus, it would then follow that the teachings of ‘505 satisfy the claim limitation with respect to where the heterodimer does not comprise an amino acid sequence of a type II membrane protein capable of binding a natural binding pair thereof as recited in instant claim 1.
Although ‘505 does not expressly teach a specific species of heterodimer comprising a TIGIT polypeptide attached to IgG1 as a dimerizing moiety as a first monomer, and a PD1 polypeptide attached to IgG4 as a dimerizing moiety as a second monomer, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to follow the teachings of ‘505 and utilize a heterodimeric protein comprising a complex of two polypeptide chains: an alpha chain and a beta chain, where the alpha chain comprises (a) a first domain comprising a butyrophilin family protein or fragment thereof; (b) a TIGIT polypeptide as a second targeting domain; and (c) a modified IgG1 containing one or more mutations as a linker thereby increasing affinity for and enhancing binding to the FcRn and improving in vivo half-life of the heterodimeric protein; and where the beta chain comprises (a) a first domain comprising a butyrophilin family protein or fragment thereof; (b) a PD1 polypeptide as a second targeting domain; and (c) a modified IgG4 containing one or more mutations as a linker thereby increasing affinity for and enhancing binding to the FcRn and improving in vivo half-life of the heterodimeric protein in order to treat cancer in a subject. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because heterodimer proteins were known to comprise a complex of two polypeptide chains where each chain comprises a second domain that comprises a targeting domain, the targeting domain being a portion of the extracellular domain of LAG-3, PD-1, TIGIT, CD19 or PSMA that is attached to a first domain via a Fc domain such as IgG1, IgG2, IgG3, and IgG4 that can be modified with one or more mutations that increase affinity for and enhance binding to the FcRn and improve in vivo half-life of the heterodimeric protein as taught by ‘505.
One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the heterodimeric protein of ‘505 comprised a complex of two polypeptide chains, an alpha chain and a beta chain (note: polypeptide chain constitutes a monomer as elected) where the alpha chain and the beta chain each independently comprise (a) a first domain comprising a butyrophilin family protein or fragment thereof; (b) a second domain comprising a targeting domain, the targeting domain being selected from (i) an antibody, antibody-like molecule, or antigen binding fragment thereof, and (ii) an extracellular domain; and (c) a linker that adjoins the first and second domain and was used to treat cancer. Therefore, utilizing an alpha chain comprising a first domain attached to a portion of the extracellular domain of TIGIT via a modified IgG1 and a beta chain comprising a first domain attached to a portion of the extracellular domain of PD1 via a modified IgG4 such that the modified IgG linkers increase affinity for and enhance binding to the FcRn and improve in vivo half-life of the heterodimeric protein would support the treatment of cancer in a subject by constituting the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
For claim 4, as discussed supra, ‘505 teaches that the linker can be a Fc domain or fragment thereof, e.g., a hinge region. When the linker is a Fc domain, ‘505 teaches that the Fc domain exhibits increased affinity for and enhanced binding to the neonatal Fc receptor (FcRn), and can include one or more mutations that increase the affinity and enhance binding to FcRn (See ‘505, [0101], [0115]). ‘505 also teaches that it is believed that increased affinity and enhanced binding to FcRn increases the in vivo half-life of the heterodimeric proteins (See ‘505, [0101]). Thus, the teachings of ‘505 satisfy the claim limitations with respect to where the Fc domain is modified to alter it’s binding to an Fc receptor and/or improve half-life of the heterodimer as recited in instant claim 4.
Additionally, even if ‘505 did not expressly teach that the Fc domain can be modified to alter it’s binding to an Fc receptor and/or improve half-life of the heterodimer, since ‘505 teaches a Fc domain as a dimerizing moiety that can be structurally modified by one or more mutations, the functional properties (i.e., altering it’s binding to a Fc receptor and/or improving half-life of the heterodimer) of the Fc domain as claimed and the known Fc domain would necessarily read upon the same. The discovery of a previously unappreciated property of a prior art composition, or a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of new functional properties (i.e., altering it’s binding to a Fc receptor and/or improving half-life of the heterodimer) which would necessarily read upon the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 4333 (CCPA 1977).
For claim 17, ‘505 teaches a pharmaceutical composition the heterodimeric protein (‘505, [0228]). Since ‘505 teaches a heterodimer of instant claim 1 without requiring additional polypeptides, and in particular, free TIGIT and PD1 polypeptides, it would necessarily follow that the heterodimer is the predominant form of the two polypeptides in the composition.
Additionally and/or alternatively, MPEP 2112-2112.02 states that when a reference discloses all the limitations of a claim except for a property or function, and the examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention but has basis for shifting the burden of proof to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). In the instant case, as discussed supra, ‘505 teaches a pharmaceutical composition comprising a heterodimer of instant claim 1. Moreover, it is noted that ‘505 teaches the required structure of the heterodimer of instant claim 1.
The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not applicants’ composition differs, and if so to what extent, from the composition taught in ‘505. The cited art taken as a whole demonstrates a reasonable probability that the composition of ‘505 is either identical or sufficiently similar to the claimed composition that whatever differences exist are not patentably significant. Therefore, with the showing of the reference, the burden of establishing non-obviousness by objective evidence is shifted to the Applicants.
Merely because a property of a composition comprising a heterodimer of instant claim 1 where the heterodimer is the predominant form of the two polypeptide in the composition is not expressly taught in a reference does not make the known composition patentable. The composition possesses properties necessarily present which might not be displayed in the tests used in ‘505. Accordingly, the teachings of ‘505 are a sufficient basis that the composition comprises a heterodimer of instant claim 1 where the heterodimer is the predominant form of the two polypeptide in the composition.
In the alternative, even if the claimed composition is not identical to the ‘505 composition with regard to some unidentified properties, the differences between that which is taught and that which is claimed are considered to be so slight that the ‘505 composition is likely to inherently possess the same properties of the claimed composition particularly in view of the similar structural characteristics which they have been shown to share, i.e., the required structure of the heterodimer. Thus, the claimed composition would have been obvious to those of ordinary skill in the art under the meaning of USC 103. Accordingly, the claimed invention as a whole was at least prima facie obvious, especially in the absence of sufficient, clear, and convincing evidence to the contrary.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THEA D' AMBROSIO whose telephone number is (571)270-1216. The examiner can normally be reached M-F 11:00 to 8:00 pm.
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, Lianko Garyu can be reached at 571-270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
Prosecution Insights