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. The amendment received on July 30, 2026, canceled claims 4 and 9; amended claim 1; and added new claims 31-34.
Claims 1-3, 6, 15-22, 24-27, and 29-34 are currently pending and claims 1-3, 15, 17, and 31-34 are under consideration as claims 18-22, 24-27, and 29-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, and claims 6 and 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 statement (IDS) submitted on August 27, 2026, is being considered by the examiner.
Response to Arguments
Applicant’s arguments, see Response, filed 7/30/26, with respect to the 112(a), written description, rejection have been fully considered and are persuasive. The rejection of claims 1-4, 9, 15, and 17 as failing to comply with the written description requirement has been withdrawn. Please note that the rejection with respect to the first and second polypeptides has been withdrawn. However, the rejection with respect to the dimerizing moiety as recited in claims 2-3 is maintained as further articulated below.
Applicant’s arguments, see Response, filed 7/30/26, with respect to the 112(b) rejection have been fully considered and are persuasive. The rejection of claim 4 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 has been withdrawn.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 2-3 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. This is a new matter rejection.
In the instant case, claim 1 was amended (cf. amendment filed 7/30/2026) to recite that the first polypeptide comprises SEQ ID NOs: 13, 31, 33, 106-107, 109, 113, or 115, and the second polypeptide comprises SEQ ID NOs: 7, 39, 41-43, 45, 47, 49, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, or 81. Applicants stated in their remarks that “[s]upport for amendment is found throughout the specification and original claims (e.g., Table 1).” Further, Applicants stated that “[n]o new matter is introduced.” (See pg. 5 of the Remarks filed on 7/30/2026). Although claims 2-3 were not amended, the amendments made to claim 1 result in claims 2-3 encompassing new matter. The support (i.e., the specification including Table 1 and original claims) do not support the heterodimer embodiments where the first polypeptide comprises SEQ ID NOs: 13, 31, or 33, and the second polypeptide comprises SEQ ID NO: 7 because these sequences already contain a dimerizing moiety attached to the polypeptides. The support does not indicate that a heterodimer that already contains a dimerizing moiety can contain a further dimerizing moiety.
Lack of Ipsis Verbis Support
The specification is void of support that would clearly support the scope of claims 2-3 in light of the instant amendment to claim 1. The specification does not teach the specifically claimed heterodimer where each of the two polypeptides contains more than one dimerizing moiety or where the heterodimer further contains a dimerizing moiety when the first polypeptide comprises SEQ ID NOs: 13, 31, or 33 and/or when the second polypeptide comprises SEQ ID NO: 7. Examination of the instant support shows that Figures 1A to 5A depict heterodimer structures where each of the two polypeptides are conjugated to a single dimerizing moiety. Since the scope of claims 2-3 is not limited to exclude when the first polypeptide comprises SEQ ID NOs: 13, 31, or 33 and/or when the second polypeptide comprises SEQ ID NO: 7, the amendment to claim 1 result in claims 2-3 encompassing heterodimers with more than 2 dimerizing moieties. Thus, the specification and original claims do not expressly describe heterodimers comprising more than 2 dimerizing moieties. In In re Ruschig, 379 F.2d 990, 154 USPQ 118 (CCPA 1967), the Court rejected a claim species that fell within a large genus. The Court analogized the genus of the compounds to a forest and the species to a tree. The Court stated “[i]t is an old custom in the woods to mark trails by making blaze marks on the trees. It is no help in finding a trail… to be confronted simply by a large number of unmarked trees. Appellants are pointing to trees. We are looking for blaze marks which single out particular trees. We see none.” Ruschig, 154 USPQ at 122. Similarly, in Fujikawa v. Wattanasin, 93 F.3d 1559, 39 USPQ2d 1895, the Federal Circuit declined to find support for a subgenus based on the discloser of a genus because the application did not contain "blazemarks" to support the subgenus. In justification for denying support, the Court stated that “just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety.” Fujikawa, 39 USPQ2d at 1905. Thus it is clear from these decisions that the specification must provide blazemarks to the new sub-genus or species.
Lack of Inherent Support
“While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure.” MPEP 2105 states that “A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a "laundry list” disclosure of every possible moiety does not constitute a written description of every species in a genus because it would not “reasonable lead” those skilled in the art to any particular species); In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967). In the instant case, as set forth above, the disclosure describes where each polypeptide comprises a dimerizing moiety, but not where the heterodimer further comprises more than two dimerizing moieties, which is the case, when the first polypeptide comprises SEQ ID NOs: 13, 31, or 33 and/or when the second polypeptide comprises SEQ ID NO: 7 (See Specification, Figures 1A to 5A). Thus, the instantly carved subgenus encompassing heterodimers comprising more than two dimerizing moieties when the first polypeptide comprises SEQ ID NOs: 13, 31, or 33 and/or when the second polypeptide comprises SEQ ID NO: 7 has not been adequately supported.
Maintained/Modified Rejections in light of Applicants’ Amendments
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 2-3 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 has been updated in light of Applicants’ amendments to be limited to the dimerizing moiety of claims 2-3.
Dependent claims 2-3 are directed to where a heterodimer comprising two polypeptides selected from PD1 and TIGIT, where the first polypeptide comprises SEQ ID NOs: 13, 31, 33, 106-107, 109, 113, or 115, and the second polypeptide comprises SEQ ID NOs: 7, 39, 41-43, 45, 47, 49, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, or 81, and where the heterodimer further comprises a dimerizing moiety attached to the two polypeptides such as an Fc domain of an antibody or fragment thereof. It is noted that the first polypeptide amino acid sequence corresponds to TIGIT and the second polypeptide amino acid sequence corresponds to PD1. Excluding SEQ ID NOs: 7, 13, 31 and 33, which already contain a Fc domain of an antibody as a dimerizing moiety, the remaining combination of sequences for the first and second polypeptides encompass any 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). 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.
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 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 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 genus.
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 dimerizing moieties meeting the claimed limitations. 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 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 2-3 do not meet the written description requirement.
Response to Arguments
Applicant's arguments filed 7/30/26 for claims 2-3 have been fully considered but they are not persuasive. As noted in the “Response to Arguments” section supra, the written description rejection has been overcome with respect to the first and second polypeptides of the heterodimer, but is maintained with respect to the dimerizing moiety.
In response to Applicant’s argument that the amendments to claim 1 overcome the written description rejection (See Applicant’s Response received on 7/30/26, pg. 5), it is found unpersuasive. MPEP §2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Additionally, the importance of structure/function correlations was highlighted by the courts (Abbvie Deutschland v. Janssen Biotech and Centorcor Biologics, App. No. 2013-1338, -1346 (Fed. Cir. , July 1, 2014)). The Abbvie case involved antibodies and written description. The court stated: “We have held that “a sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568– 69).”. The courts then further stated: “With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus.” (emphasis added) and then state: " Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation. Instead, Abbvie used a trial and error approach to modify individual amino acids in order to improve the IL-12 binding affinity. Moreover, the ’128 and ’485 patents do not describe any common structural features of the claimed antibodies. The asserted claims attempt to claim every fully human IL-12 antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity, and cover an antibody as different as Stelara, whereas the patents do not describe representative examples to support the full scope of the claims.”
In the instant case, without an indication of a core structure, sequence or residues that would be necessary in order for moiety, which includes non-proteinaceous and proteinaceous moieties, to function in altering binding to a Fc receptor, reducing an immune activating function and/or improving the half-life of the heterodimer, it would be difficult for a skilled artisan to envision the correlation between structure and function for the whole genus and/or to predict what would be covered by the functionally claimed genus because Applicants have failed to provide a representative number of species to support the scope of the whole genus. Accordingly, the rejection is maintained for claims 2-3 as Applicant’s argument is found unpersuasive.
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 1-3, 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 (cited in the Action mailed on 4/30/26). Please note that the rejection has been updated in light of Applicants’ amendments.
For claims 1-3 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 second polypeptide comprising SEQ ID NO: 42, 43, 47, 53, 55, 57, 65, 69, or 73 as a PD-1 polypeptide, as discussed supra, ‘505 teaches that the targeting domain can be a portion of the extracellular domain of PD-1 (See ‘505, [0075], [0094], [0121], [0128], [0135]-[0136], [0138]-[0139]). A specific embodiment of a polypeptide chain comprising PD1 fused to BTNL3 has the amino acid sequence of SEQ ID NO: 33 (See ‘505, [0348]). When comparing ‘505’s SEQ ID NO: 33 with instant SEQ ID NOs: 42, 43, 47, 53, 55, 57, 65, 69, or 73, there is 100% identity with each sequence. Since the scope of the instant second polypeptide “comprises” one of the recited amino acid sequences, the fusion to BTNL3 is encompassed by the instant second polypeptide. Thus, the targeting domain comprising a portion of the extracellular domain of PD-1 where the amino acid sequence of the PD1 targeting domain comprises instant SEQ ID NO: 42, 43, 47, 53, 55, 57, 65, 69, or 73 as recited in instant claim 1.
With respect to a first polypeptide comprising SEQ ID NO: 107, 113, or 115 as a TIGIT polypeptide, as discussed supra, ‘505 teaches that the targeting domain can be a portion of the extracellular domain of TIGIT (See ‘505, [0075], [0094], [0121], [0128], [0135]-[0136], [0138]-[0139]). A specific embodiment of a polypeptide chain comprising TIGIT fused to BTNL3 has the amino acid sequence of SEQ ID NO: 28 (See ‘505, [0346]). When comparing ‘505’s SEQ ID NO: 28 with instant SEQ ID NOs: 107, 113, or 115, there is 100% identity with each sequence. Since the scope of the instant first polypeptide “comprises” one of the recited amino acid sequences, the fusion to BTNL3 is encompassed by the instant first polypeptide. Thus, the targeting domain comprising a portion of the extracellular domain of TIGIT where the amino acid sequence of the TIGIT targeting domain comprises instant SEQ ID NO: 107, 113, or 115 as recited in instant claim 1.
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 comprising instant SEQ ID NO: 107, 113, or 115 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 comprising instant SEQ ID NO: 42, 43, 47, 53, 55, 57, 65, 69, or 73 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 comprising instant SEQ ID NOs: 107, 113, or 115 via a modified IgG1 and a beta chain comprising a first domain attached to a portion of the extracellular domain of PD1 comprising instant SEQ ID NO: 42, 43, 47, 53, 55, 57, 65, 69, or 73 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 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.
Response to Arguments
Applicant's arguments filed 7/30/26 for claims 1-3, 15, and 17 as being unpatentable over the ‘505 reference have been fully considered but they are not persuasive for the following reasons.
In response to Applicant’s argument, i.e., the ‘505 reference fails to teach or suggest all of the claimed limitations as admitted by the Examiner stating in the rejection “’505 does not expressly teach a specific species of heterodimer comprising a TIGIT polypeptide attached to a IgG1 as a dimerizing moiety as a first monomer, and a PD1 polypeptide attached to IgG4 as a dimerizing moiety as a second monomer”, and thus, amended claim 1 is not obvious over ‘505 (See Applicant’s Response received on 7/30/26, pg. 6-7), it is found unpersuasive. It is acknowledged that ‘505 does not teach or suggest a specific embodiment of a heterodimer as instantly claimed. However, Applicants are respectfully reminded that the rejection is based on obviousness. Pursuant to MPEP 2142, 35 USC 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references (emphasis added). Since the rejection is based on obviousness, it is unnecessary for every claim limitation to be taught and/or suggested in a specific embodiment. If every claim limitation is taught in a specific embodiment, the rejection would be one of anticipation, not obvious. Additionally, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as discussed supra in the 103 rejection, the Examiner stating that ‘505 does not expressly teach a specific species of heterodimer…., does not correspond that to stating that the claim limitations are not suggested by the teachings of ‘505. Rather, when considering the teachings of ‘505 as a whole, they are suggestive of the claim limitations as recited in instant claims 1-3, 15, and 17. Pursuant to MPEP 2141, “[a] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984). As discussed supra, ‘505 expressly teaches a heterodimer comprising two polypeptide chains where a chain can contain a fusion protein that contains a targeting domain comprising a portion of an extracellular domain of PD1 or TIGIT. ‘505 also expressly teaches specific polypeptide chains comprising where one example comprising instant SEQ ID NO: 107, 113, or 115 as a TIGIT polypeptide, and another example comprising instant SEQ ID NO: 42, 43, 47, 53, 55, 57, 65, 69, or 73. Thus, contrary to Applicant’s argument, when considering ‘505’s teachings as a whole, the ‘505 teachings suggest all the claim limitations.
Accordingly, the rejection of claims 1-3, 15, and 17 is maintained as Applicant’s argument is found unpersuasive.
Allowable Subject Matter
Claims 31-34 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. It is noted that there is no teaching or suggestion in the art to arrive at the specifically claimed sequences. The closest prior art is Schreiber et al. US Publication No. 2020/0216505 A1 published on July 9, 2020 (cited in Action mailed on 4/30/26). ‘505 teaches a heterodimer comprising a complex of two polypeptide chains, an alpha and beta chain, where each chain comprises a targeting domain comprising a portion of an extracellular 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]). Plus, ‘505’s teaches that a 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 where the linker facilitates heterodimerization and can be hinge region of an antibody, e.g., of IgG including IgG1 and IgG4, or a Fc domain of an antibody such as IgG including subclasses such as IgG1 and IgG4 (See ‘505, [0109], [0094], [0111]). However, ‘505 does not teach the specific amino acid modifications/substitutions made to specific residues within claimed SEQ ID NOs: 7, 13, 31, 33, 49, and 109. Since there is no teaching or suggesting in the art to achieve 100% identity to the first and/or second polypeptide sequences claimed in claims 31-34, the scope of the claims is free of the prior art.
Conclusion
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 THEA D' AMBROSIO whose telephone number is (571)270-1216. The examiner can normally be reached M-F 11:00 to 8:00 pm.
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
