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 .
Claims 1-6, 9-18 and 25-27 are pending.
Claims 17-18 and 25-27 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-6 and 9-16, drawn to a bispecific scFv construct agonizing both Cd3 and CD28 pathways, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/092,410, filed Oct 15, 2020, is acknowledged.
Objection and Rejection Withdrawn
The objection to claim 12 is withdrawn in view of the claim amendment.
The rejection of claims 4, 9 and 14-16 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in light of the claim amendment.
Claim rejections under - 35 U.S.C. 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 1-6 and 9-15 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.
MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.”
Claim 1 encompass any bispecific scFv construct agonizing both CD3 and CD28 pathways, wherein the anti-CD28 scFv is at the N-terminus of the construct and the anti-CD3 scFv is at the C-terminus of the construct.
Claim 2 encompass the construct of claim 1, wherein the construct is soluble.
Claim 3 encompass the construct of claim 1 or 2, wherein the construct activates, expands, and differentiates human T cells ex vivo.
Claim 4 encompass the construct of claim 3, wherein the construct is active at concentrations in the femtomolar range between about 10 to about 500 fM.
Claim 5 encompass the construct of claim 1, wherein the construct promotes the preferential growth of human CD8+ T cells over the course of 12 days in comparison to methods involving immobilized anti-CD3 mAb/soluble anti-CD28 mAb or soluble anti CD3/CD28 mAb complexes.
Claim 6 encompass the construct of claim 1, wherein the construct favors the expansion of a CD8+CD27+ T cell phenotype.
Claim 9 encompass the construct of claim 1, comprising one or more flexible linkers.
Claim 10 encompass the construct of claim 9, comprising a flexible linker between each heavy and light chain domain of each scFv as well as a flexible linker between each scFv.
Claim 11 encompass the construct of claim 1, wherein the construct engages both signals for TCR activation and co-stimulation at a molar ratio of 1:1.
Claim 12 encompass the construct of claim 1, comprising a purification and/or detection tag.
Claim 13 encompass the construct of claim 12, comprising a histidine tag.
Claim 14 encompass the construct of claim 1, comprising or consisting of a polypeptide having at least 80% sequence identity to SEQ ID NO:1: DIVLTQSPASLAVSLGQRATISCRASESVEYYVTSLMQWYQQKPGQPPKLLIFAASNV ESGVPARFSGSGSGTNFSLNIHPVDEDDVAMYFCQQSRKVPYTFGGGTKLEIKRGG GGSGGGGSGGGGSQVKLQQSGPGLVTPSQSLSITCTVSGFSLSDYGVHWVRQSPG QGLEWLGVIWAGGGTNYNSALMSRKSISKDNSKSQVFLKMNSLQADDTAVYYCARD KGYSYYYSMDYWGQGTTVTVSSASTKGPSVFPLAPSSGSGGGGSGGGGSGGGGS DIKLQQSGAELARPGASVKMSCKTSGYTFTRYTMHWVKQRPGQGLEWIGYINPSRG YTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQG TTLTVSSVEGGSGGSGGSGGSGGVDDIQLTQSPAIMSASPGEKVTMTCRASSSVSY MNWYQQKSGTSPKRWIYDTSKVASVPYRFSGSGSGTSYSLTISSMEAEDAATYYCQ QWSSNPLTFGAGTKLELKHHHHHH.
Claim 15 encompass the construct of claim 14, comprising a polypeptide having at least 85, 90, 95, 96, 97, 98, or 99% identity to SEQ ID NO:1.
The specification discloses just one bispecific scFv construct (T cell expansion protein or T-CEP)
comprising the amino acid sequence of SEQ ID NO: 1 that binds to just human CD28 and human CD3 extracellular domains, see Para. [0040] to [0042]. The Soluble T Cell Activator that Favors the Ex Vivo Expansion of Multifunctional Human CD8+CD27+ T Cells over the course of 12 days compared to an established protocol where an immobilized agonistic anti-CD3 mAb is combined with a soluble anti-CD28 mAb or a combined solution of monospecific tetrameric antibody complexes (TACs).
The specification discloses:
[0119] A 60 kDa soluble T cell expansion protein (T-CEP) was designed by fusing together two distinct single chain variable fragments (scFvs) that respectively bind to human CD3 and human CD28 and act as agonists in activating both signaling pathways (FIG. 1A). These selected scFv sequences have independently been shown to agonise CD3.sup.23 and CD28.sup.24 respectively, and accordingly activate human T cells. These scFvs were linked together using a short flexible spacer (SSGSGGGGSGGGGSGGGGS), similar to previously described linkers..sup.25 A 6-histidine tag was added at the C terminus of the construct for purification purposes and for detecting the construct (FIG. 1A). Of note, two T-CEP constructs were originally built to assess whether the orientation (i.e., the anti-CD28 scFv at the C-terminus or the N-terminus of the construct) had an impact on their functional properties. The construct as depicted in FIG. 1A, with the scFv targeting CD28 at the N-terminus, and the CD3 scFv placed at its C-terminus was ultimately chosen as the lead compound, due to higher production yields and more potent T cell expansion activity (results not shown). T-CEP was expressed as a secreted, soluble protein produced in HEK293 cells [Expi293 system] and purified using immobilized metal affinity chromatography. Its purity was confirmed by SDS-PAGE and Western blot analysis, migrating as a 60 kDa band, corresponding to the expected molecular weight of T-CEP based on its amino acid sequence (FIG. 1B).
Functional Characterization of T-CEP on Human T Cells
[0123] T-CEP Induces the Proliferation of Both Human CD4.sup.+ and CD8.sup.+ T Cells at Very Low Concentrations
[0124] In order to determine the optimal working concentration of T-CEP, T cells isolated from human PBMCs were stained with carboxyfluorescein succinimidyl ester (CFSE; a cell proliferation tracer) and stimulated with T-CEP for 5 days over a range of T-CEP concentrations (50 μg/ml up to 10 μg/ml). Their proliferative activity, as evidence by a loss in CFSE signal, was analyzed by flow (results not shown). Comparable T cell proliferative activity by T-CEP was noted for concentrations as low as 500 μg/ml, however for all subsequent studies, a T-CEP concentration of 10 ng/mL (170 fM) was selected as it consistently yielded maximal T cell proliferation (FIG. 4A). Interestingly, the concentration of soluble T-CEP required to cause a full expansion of human T cells ex vivo was 150-fold less (in g/l) than required for TACs (when used per manufacturer instruction, ˜1.5 μg/ml, ˜2.5 pM). This T-CEP concentration was also far less than the optimal doses of immobilized αCD3 (i αCD3) (10 μg/ml) and soluble αCD28 (s αCD28) (1 μg/ml) mAbs. As expected, unstimulated T cells did not proliferate while anti-CD3 without co-stimulation led to a much-reduced level of both CD4.sup.+ and CD8.sup.+ human T cell proliferation.
However, the specification does not describe the structure, e.g., amino acid sequences of heavy and light chain variable region of any and all possible bispecific scFv constructs that bind to any mammalian CD28 and CD3 that correlated with the claimed functions, i.e., agonizing both CD3 and CD28 pathways, activates, expands, and differentiates any human T cells ex vivo, activates at concentration in the femtomolar range between about 10 to about 500 fM or promotes the preferential expansion of human CD8+ T cells over the course of 12 days or favors the expansion of any CD8+CD27+ T cell phenotype. The structure-function correlation set forth in the disclosure does not clearly allow persons of ordinary skill in the art to recognize that the applicant has in fact invented what is claimed because the disclosure only sets forth adequate written description for just one bispecific scFv construct comprising SEQ ID NO: 1 that agonizes both human CD3 and human CD28, activates, expands and differentiates human CD8+ CD27+ T cells ex vivo at a concentration of 10 ng/ml (170 fM) over the course of 12 days. Thus, the functional definition (i.e., agonizing both CD3 and CD28 pathways, activates, expands, and differentiates any human T cells ex vivo, activates at concentration in the femtomolar range between about 10 to about 500 fM, promotes the preferential growth of human CD8+ T cells over the course of 12 days or favors expansion of any CD28+CD27+ T cells cannot be correlated with the disclosed structure.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. of record, Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 2003 Nov 14;334(1): 103-118; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Piche-Nicholas et al., (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
In Abbvie v. Centocor (Fed. Cir. 2014), the Court held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of just 11-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that 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.
With regard to a representative number of species, the application discloses just one bispecific scFv construct comprising SEQ ID NO: 1 that agonizes both human CD3 and human CD28, activates, expands and differentiates human CD8+ CD27+ T cells ex vivo at a concentration of 10 ng/ml (170 fM) over the course of 12 days.
However, the specification does not describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed bispecific scFv construct themselves having the claimed functions to demonstrate possession at the time of filing. Thus, a representative number of species and relevant identifying characteristics of each are NOT provided in the present application.
A “patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”), see Noelle v. Lederman, 69 USPQ2d 1508 1514 (CAFC 2004), (citing Enzo Boichem II, 323 F. 3d at 965; Regents, 119 F.3d at 1568), MPEP 2163.IIAii
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010). In light of the number of representative number of species provided and in light of Lloyd, Edwards and Piche-Nicholas et al as to the lack of structural features common to the members of the genus, one skilled in the art would not recognize that applicant was in possession of the genus at the time of filing.
Regarding construct comprising a polypeptide having at least 80, 85, 90, or 95% identity to SEQ ID NO: 1 (claims 14 and 15), the specification does not teach where and what amino acid within the full-length sequence of SEQ ID NO: 1 to be substituted, deleted, added or a combination thereof such that the modified polypeptide having at least 80, 85, 90 or 95% identity to SEQ ID NO: 1 still maintains the claimed function, e.g., agonizing both CD3 and CD28 pathways, activates, expands, and differentiates any human T cells ex vivo, activates at concentration in the femtomolar range between about 10 to about 500 fM, such as about 170 fM, promotes the preferential growth of human CD8+ T cells over the course of 12 days.
It is well established in the art that minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by the US Pat No 7,084,257.
The 7,084,257 patent teaches an isolated human monoclonal antibody comprising a heavy chain and a light chain wherein the reference light chain is at least 95.9% identical to the claimed SEQ ID NO: 144 and paired with any heavy chain and yet the reference human monoclonal antibody binds to human interferon gamma instead of an epitope LEEKKGNYVVTDHC (SEQ ID NO: 56) on EGFRvIII (see entire document, reference SEQ ID NO: 92, bottom sequence in alignment set forth below, in particular).
There are no working examples. It is unpredictable which modification such as any substitution, deletion, addition or a combination thereof still maintains binding to human CD28 and human CD3, much less agonizing any CD3 and CD28 pathways.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “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, whatever 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).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, only (1) a bispecific scFv construct agonizing both human CD3 and human CD28 pathway, wherein the scFv construct comprises the amino acid sequence of SEQ ID NO: 1, (2) Said bispecific scFv construct is soluble, (3) The construct above wherein the construct activates, expands, and differentiates human T cells ex vivo, (4) The construct above wherein the construct is active at a concentration of about 170 fM, (5) The construct above wherein the construct promotes the growth of human CD8+ CD27+ T cells over the course of 12 days, (6) The construct above wherein the anti-CD28 scFv is at the N-terminus of the construct and the anti-CD3 scFv is at the C-terminus of the construct, (7) The construct above engages both signals for TCR activation and co-stimulation at a molar ratio of 1:1, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Applicant’s arguments, filed August 7, 2026, have been fully considered but are not found persuasive.
Applicant’s position is that claim 1 has been amended to further clarify the structure of the construct, which is consistent with the previously submitted claims and the teachings and exemplified data of the specification as originally filed.
Moreover, Applicant submits that claim 1 as amended satisfies the written description requirement as the claim is drawn to a specific orientation of the components of the claimed bispecific construct. This is well within the teachings of the originally filed specification. In this regard, the specification does not disclose just one T-CEP construct as the Office Action alleges but at least two constructs were tested (see, for example, paragraph [0119] of the application). The construct thus claimed is therefore but one of the exemplified embodiments of the specification as originally filed.
In further support for the claims satisfying the written description requirement, the specification further discloses a correlation between function and structure. For example, Example 1 exemplifies that the claimed orientation anti-CD28 - anti-CD3 (as shown in Fig.1A) is better than anti-CD3-anti-CD28 in terms of higher production yields and T cell expansion activity (see, e.g., paragraph [0119] of the application). In another example, the specification describes the structure of the claimed construct in Fig.1A which correlates with the claimed function and concentration (see, e.g., paragraph [0124] of the application). Thus, the specification has sufficiently disclosed the correlation between the structure and function of the claimed constructs.
With regard to sequence identity (per claims 14 and 15), the skilled person would know how to make variants of SEQ ID NO:1 (or SEQ ID NO:2) with the claimed sequence identity. As the claims are to be read in view of the specification as a whole, Applicant submits that at least paragraph [0067] of the application, for example, defines 'variants'. As such, it would be well within the purview of the skilled person, having the teachings of the application (including the exemplified embodiments and definitions), in addition to their knowledge in the field of antibody manufacturing and use, especially in light of the various computational programs available to said person to test the produced constructs, to practice the invention and make variants that fall within the scope of the claims. Thus, with the construct design shown in Fig.1A and its sequence shown by SEQ ID NO: 1 or 2, Applicant submits that the skilled person would make and use the claimed construct without undue experimentation.
Finally, the specification provides a detailed description of the manner of making and using the claimed constructs. For example, Example 1 provides a detailed description of the design and the method of producing the claimed constructs as well as their use in antagonizing the claimed pathways. Thus, coupled with the information above, the specification has provided ample description of the manner of making and using the constructs according to amended claim 1, such that the skilled person is equipped to practice the scope of the claims. For at least these reasons, the specification provides sufficient written description for claim 1 as amended.
Claim 7 is cancelled. The rejection with respect to this claim is thereby rendered moot. Claims 2 to 6 and 9 to 16 depend directly or indirectly from claim 1. Thus, the specification provides written description for these claims for at least the same reasons it does for claim 1.
Accordingly, Applicant respectfully requests that the rejection of claims 1 to 7 and 9 to 15 under 35 U.S.C. §112(a) be withdrawn.
In response, the amendment to claims 1 and 7 is acknowledged.
Claim 1 encompass any bispecific scFv construct agonizing any CD3 and any CD28 pathways, wherein the anti-CD28 scFv is at the N-terminus of the construct and the anti-CD3 scFv is at the C-terminus of the construct.
Claim 2 encompass the construct of claim 1, wherein the construct is soluble.
Claim 3 encompass the construct of claim 1 or 2, wherein the construct activates, expands, and differentiates human T cells ex vivo.
Claim 4 encompass the construct of claim 3, wherein the construct is active at concentrations in the femtomolar range between about 10 to about 500 fM.
Claim 5 encompass the construct of claim 1, wherein the construct promotes the preferential growth of human CD8+ T cells over the course of 12 days in comparison to methods involving immobilized anti-CD3 mAb/soluble anti-CD28 mAb or soluble anti CD3/CD28 mAb complexes.
Claim 6 encompass the construct of claim 1, wherein the construct favors the expansion of a CD8+CD27+ T cell phenotype.
Claim 9 encompass the construct of claim 1, comprising one or more flexible linkers.
Claim 10 encompass the construct of claim 9, comprising a flexible linker between each heavy and light chain domain of each scFv as well as a flexible linker between each scFv.
Claim 11 encompass the construct of claim 1, wherein the construct engages both signals for TCR activation and co-stimulation at a molar ratio of 1:1.
Claim 12 encompass the construct of claim 1, comprising a purification and/or detection tag.
Claim 13 encompass the construct of claim 12, comprising a histidine tag.
Claim 14 encompass the construct of claim 1, comprising or consisting of a polypeptide having at least 80% sequence identity to SEQ ID NO:1: DIVLTQSPASLAVSLGQRATISCRASESVEYYVTSLMQWYQQKPGQPPKLLIFAASNV ESGVPARFSGSGSGTNFSLNIHPVDEDDVAMYFCQQSRKVPYTFGGGTKLEIKRGG GGSGGGGSGGGGSQVKLQQSGPGLVTPSQSLSITCTVSGFSLSDYGVHWVRQSPG QGLEWLGVIWAGGGTNYNSALMSRKSISKDNSKSQVFLKMNSLQADDTAVYYCARD KGYSYYYSMDYWGQGTTVTVSSASTKGPSVFPLAPSSGSGGGGSGGGGSGGGGS DIKLQQSGAELARPGASVKMSCKTSGYTFTRYTMHWVKQRPGQGLEWIGYINPSRG YTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQG TTLTVSSVEGGSGGSGGSGGSGGVDDIQLTQSPAIMSASPGEKVTMTCRASSSVSY MNWYQQKSGTSPKRWIYDTSKVASVPYRFSGSGSGTSYSLTISSMEAEDAATYYCQ QWSSNPLTFGAGTKLELKHHHHHH.
Claim 15 encompass the construct of claim 14, comprising a polypeptide having at least 85, 90, 95, 96, 97, 98, or 99% identity to SEQ ID NO:1.
The specification discloses just one bispecific scFv construct (T cell expansion protein or T-CEP)
comprising the amino acid sequence of SEQ ID NO: 1 that binds to just human CD28 and human CD3 extracellular domains and agonizes both human CD3 and human CD28, activates, expands and differentiates human CD8+ CD27+ T cells ex vivo at a concentration of 10 ng/ml (170 fM) over the course of 12 days, see Para. [0040] to [0042].
However, the specification does not describe the structure, e.g., amino acid sequences of heavy and light chain variable region of any and all possible bispecific scFv constructs that bind to any mammalian CD28 and CD3 that correlated with the claimed functions, i.e., agonizing both CD3 and CD28 pathways, activates, expands, and differentiates any T cells ex vivo, activates at concentration in the femtomolar range between about 10 to about 500 fM or promotes the preferential expansion of human CD8+ T cells over the course of 12 days or favors the expansion of any CD8+CD27+ T cell phenotype.
The structure-function correlation set forth in the disclosure does not clearly allow persons of ordinary skill in the art to recognize that the applicant has in fact invented what is claimed because the disclosure only sets forth adequate written description for just one bispecific scFv construct comprising SEQ ID NO: 1 that agonizes both human CD3 and human CD28, activates, expands and differentiates human CD8+ CD27+ T cells ex vivo at a concentration of 10 ng/ml (170 fM) over the course of 12 days. Thus, the functional definition (i.e., active at concentration in the femtomolar range between about 10 to about 500 fM (claim 4), agonizing both CD3 and CD28 pathways, activates, expands, and differentiates any human T cells ex vivo (claim 3), promotes the preferential growth of human CD8+ T cells over the course of 12 days (claim 5) or favors expansion of any CD28+CD27+ T cells (claim 6) or engages both signals for TCR activation and co-stimulation at a molar ratio of 1:1 (claim 11) cannot be correlated with the disclosed structure.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. of record, Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 2003 Nov 14;334(1): 103-118; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Piche-Nicholas et al., (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
In Abbvie v. Centocor (Fed. Cir. 2014), the Court held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of just 11-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that 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.
With regard to a representative number of species, the application discloses just one bispecific scFv construct comprising SEQ ID NO: 1 that agonizes both human CD3 and human CD28, activates, expands and differentiates human CD8+ CD27+ T cells ex vivo at a concentration of 10 ng/ml (170 fM) over the course of 12 days.
However, the specification does not describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed bispecific scFv construct themselves having the claimed functions to demonstrate possession at the time of filing. Thus, a representative number of species and relevant identifying characteristics of each are NOT provided in the present application.
Here, applicant is claiming bispecific scFv constructs having agonizing activities by describing the antigens, e.g., CD3 and CD28 to which the bispecific scFv antibody binds but does not describe the structure-identifying information about the claimed bispecific scFv construct, nor describe a representative number of species falling within the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed bispecific scFv construct themselves.
Regarding construct comprising a polypeptide having at least 80, 85, 90, or 95% identity to SEQ ID NO: 1 (claims 14 and 15), the specification does not teach where and what amino acid within the full-length sequence of SEQ ID NO: 1 to be substituted, deleted, added or a combination thereof such that the modified polypeptide having at least 80, 85, 90 or 95% identity to SEQ ID NO: 1 still maintains the claimed function, e.g., agonizing both CD3 and CD28 pathways, activates, expands, and differentiates any human T cells ex vivo, activates at concentration in the femtomolar range between about 10 to about 500 fM, such as about 170 fM, promotes the preferential growth of human CD8+ T cells over the course of 12 days.
It is well established in the art that minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by the US Pat No 7,084,257.
The 7,084,257 patent (of record) teaches an isolated human monoclonal antibody comprising a heavy chain and a light chain wherein the reference light chain is at least 95.9% identical to the claimed SEQ ID NO: 144 and paired with any heavy chain and yet the reference human monoclonal antibody binds to human interferon gamma instead of an epitope LEEKKGNYVVTDHC (SEQ ID NO: 56) on EGFRvIII (see entire document, reference SEQ ID NO: 92, bottom sequence in alignment set forth below, in particular). There are no working examples. It is unpredictable which modification such as any substitution, deletion, addition or a combination thereof still maintains binding to human CD28 and human CD3, much less maintaining agonizing to both CD3 and CD28 pathways.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
While the Federal Circuit has recognized that “the written description requirement can in some cases be satisfied by functional description,” it has made clear that “such functional description can be sufficient only if there is also a structure-function relationship known to those of ordinary skill in the art.” In re Wallach, 378 F.3d 1330, 1335 (Fed. Cir. 2004); see also, Enzo Biochem, Inc. v. Gen-Probe, Inc.,323 F.3d 956, 964 (Fed. Cir. 2002) (holding that the written description requirement would be satisfied “if the functional characteristic of preferential binding . . . were coupled with a disclosed correlation between that function and a structure that is sufficiently known or disclosed”); Amgen Inc. v. Sanofi, 782 F.3d 1367, 1378 (Fed. Cir. 2017) (holding that an “adequate written description must contain enough information about the actual makeup of the claimed products”). Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010).
A representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
Given the well-known high level of polymorphism of antibodies, the disclosure of just one specific of bispecific scFv antibody that binds to just human CD3 and human CD28 is not representative of the genus. One of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of bispecific scFv antibody construct comprising any anti-CD28 scFv at the N-terminus of the construct and any anti-CD3 scFv at the C-terminus of the construct wherein the construct agonizing any and all CD3 and CD28 pathways of any species.
For these reasons, the rejection is maintained.
Claims 1-6 and 9-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (1) a bispecific scFv construct agonizing both human CD3 and human CD28 pathway, wherein the scFv construct comprises the amino acid sequence of SEQ ID NO: 1, (2) Said bispecific scFv construct is soluble, (3) The construct above wherein the construct activates, expands, and differentiates human T cells ex vivo, (4) The construct above wherein the construct is active at a concentration of about 170 fM, (5) The construct above wherein the construct promotes the growth of human CD8+ CD27+ T cells over the course of 12 days, (6) The construct above wherein the anti-CD28 scFv is at the N-terminus of the construct and the anti-CD3 scFv is at the C-terminus of the construct, (7) The construct above engages both signals for TCR activation and co-stimulation at a molar ratio of 1:1, does not reasonably provide enablement for any bispecific scFv construct agonizing both any CD3 and any CD28 pathways as set forth in claims 1-6 and 9-16. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 1 encompass any bispecific scFv construct agonizing both CD3 and CD28 pathways, wherein the anti-CD28 scFv is at the N-terminus of the construct and the anti-CD3 scFv is at the C-terminus of the construct.
Claim 2 encompass the construct of claim 1, wherein the construct is soluble.
Claim 3 encompass the construct of claim 1 or 2, wherein the construct activates, expands, and differentiates human T cells ex vivo.
Claim 4 encompass the construct of claim 3, wherein the construct is active at concentrations in the femtomolar range between about 10 to about 500 fM.
Claim 5 encompass the construct of claim 1, wherein the construct promotes the preferential growth of human CD8+ T cells over the course of 12 days in comparison to methods involving immobilized anti-CD3 mAb/soluble anti-CD28 mAb or soluble anti CD3/CD28 mAb complexes.
Claim 6 encompass the construct of claim 1, wherein the construct favors the expansion of a CD8+CD27+ T cell phenotype.
Claim 9 encompass the construct of claim 1, comprising one or more flexible linkers.
Claim 10 encompass the construct of claim 9, comprising a flexible linker between each heavy and light chain domain of each scFv as well as a flexible linker between each scFv.
Claim 11 encompass the construct of claim 1, wherein the construct engages both signals for TCR activation and co-stimulation at a molar ratio of 1:1.
Claim 12 encompass the construct of claim 1, comprising a purification and/or detection tag.
Claim 13 encompass the construct of claim 12, comprising a histidine tag.
Claim 14 encompass the construct of claim 1, comprising or consisting of a polypeptide having at least 80% sequence identity to SEQ ID NO:1: DIVLTQSPASLAVSLGQRATISCRASESVEYYVTSLMQWYQQKPGQPPKLLIFAASNV ESGVPARFSGSGSGTNFSLNIHPVDEDDVAMYFCQQSRKVPYTFGGGTKLEIKRGG GGSGGGGSGGGGSQVKLQQSGPGLVTPSQSLSITCTVSGFSLSDYGVHWVRQSPG QGLEWLGVIWAGGGTNYNSALMSRKSISKDNSKSQVFLKMNSLQADDTAVYYCARD KGYSYYYSMDYWGQGTTVTVSSASTKGPSVFPLAPSSGSGGGGSGGGGSGGGGS DIKLQQSGAELARPGASVKMSCKTSGYTFTRYTMHWVKQRPGQGLEWIGYINPSRG YTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQG TTLTVSSVEGGSGGSGGSGGSGGVDDIQLTQSPAIMSASPGEKVTMTCRASSSVSY MNWYQQKSGTSPKRWIYDTSKVASVPYRFSGSGSGTSYSLTISSMEAEDAATYYCQ QWSSNPLTFGAGTKLELKHHHHHH.
Claim 15 encompass the construct of claim 14, comprising a polypeptide having at least 85, 90, 95, 96, 97, 98, or 99% identity to SEQ ID NO:1.
Enablement is not commensurate in scope with claims as how to make and use any bispecific scFv construct above for activates, expands and differentiate any human T cells ex vivo.
The specification teaches just one bispecific scFv construct (T cell expansion protein or T-CEP)
comprising the amino acid sequence of SEQ ID NO: 1 that binds to just human CD3 and human CD28 extracellular domains, see Para. [0040] to [0042]. The Soluble T Cell Activator that Favors the Ex Vivo Expansion of Multifunctional Human CD8+CD27+ T Cells over the course of 12 days compared to an established protocol where an immobilized agonistic anti-CD3 mAb is combined with a soluble anti-CD28 mAb or a combined solution of monospecific tetrameric antibody complexes (TACs).
The specification discloses:
[0119] A 60 kDa soluble T cell expansion protein (T-CEP) was designed by fusing together two distinct single chain variable fragments (scFvs) that respectively bind to human CD3 and human CD28 and act as agonists in activating both signaling pathways (FIG. 1A). These selected scFv sequences have independently been shown to agonise CD3.sup.23 and CD28.sup.24 respectively, and accordingly activate human T cells. These scFvs were linked together using a short flexible spacer (SSGSGGGGSGGGGSGGGGS), similar to previously described linkers..sup.25 A 6-histidine tag was added at the C terminus of the construct for purification purposes and for detecting the construct (FIG. 1A). Of note, two T-CEP constructs were originally built to assess whether the orientation (i.e., the anti-CD28 scFv at the C-terminus or the N-terminus of the construct) had an impact on their functional properties. The construct as depicted in FIG. 1A, with the scFv targeting CD28 at the N-terminus, and the CD3 scFv placed at its C-terminus was ultimately chosen as the lead compound, due to higher production yields and more potent T cell expansion activity (results not shown). T-CEP was expressed as a secreted, soluble protein produced in HEK293 cells [Expi293 system] and purified using immobilized metal affinity chromatography. Its purity was confirmed by SDS-PAGE and Western blot analysis, migrating as a 60 kDa band, corresponding to the expected molecular weight of T-CEP based on its amino acid sequence (FIG. 1B).
Functional Characterization of T-CEP on Human T Cells
[0123] T-CEP Induces the Proliferation of Both Human CD4.sup.+ and CD8.sup.+ T Cells at Very Low Concentrations
[0124] In order to determine the optimal working concentration of T-CEP, T cells isolated from human PBMCs were stained with carboxyfluorescein succinimidyl ester (CFSE; a cell proliferation tracer) and stimulated with T-CEP for 5 days over a range of T-CEP concentrations (50 μg/ml up to 10 μg/ml). Their proliferative activity, as evidence by a loss in CFSE signal, was analyzed by flow (results not shown). Comparable T cell proliferative activity by T-CEP was noted for concentrations as low as 500 μg/ml, however for all subsequent studies, a T-CEP concentration of 10 ng/mL (170 fM) was selected as it consistently yielded maximal T cell proliferation (FIG. 4A). Interestingly, the concentration of soluble T-CEP required to cause a full expansion of human T cells ex vivo was 150-fold less (in g/l) than required for TACs (when used per manufacturer instruction, ˜1.5 μg/ml, ˜2.5 pM). This T-CEP concentration was also far less than the optimal doses of immobilized αCD3 (i αCD3) (10 μg/ml) and soluble αCD28 (s αCD28) (1 μg/ml) mAbs. As expected, unstimulated T cells did not proliferate while anti-CD3 without co-stimulation led to a much-reduced level of both CD4.sup.+ and CD8.sup.+ human T cell proliferation.
However, the specification does not teach the structure, e.g., amino acid sequences of heavy and light chain variable region of any and all possible bispecific scFv constructs that bind any and all mammalian CD3 and CD28 and having the claimed functions, e.g., active at concentration in the femtomolar range between about 10 to about 500 fM (claim 4), agonizing both CD3 and CD28 pathways, activates, expands, and differentiates any human T cells ex vivo (claim 3), promotes the preferential growth of human CD8+ T cells over the course of 12 days (claim 5) or favors expansion of any CD28+CD27+ T cells (claim 6) or engages both signals for TCR activation and co-stimulation at a molar ratio of 1:1 (claim 11). The persons of ordinary skill in the art cannot predict which undisclosed bispecific scFv construct comprising which anti-CD28 scFv at the N-terminus and which anti-CD3 scFv at the C-terminus has agonizing activities to both CD3 and CD28, activates, expands, and differentiates any human T cells ex vivo, activates at concentration in the femtomolar range such as between about 10 to about 500 fM, promotes the preferential growth of human CD8+ T cells over the course of 12 days.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. of record, Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 2003 Nov 14;334(1): 103-118; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Piche-Nicholas et al., (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
Regarding construct comprising or consisting of a polypeptide having at least 80, 85, 90, 95% identity to SEQ ID NO: 1 (claims 14 and 15), the specification does not teach where and what amino acid within the full-length sequence of SEQ ID NO: 1 to be substituted, deleted, added or a combination thereof such that the modified polypeptide having at least 80, 85, 90 or 95% identity to SEQ ID NO: 1 still maintains the claimed function, e.g., agonizing both CD3 and CD28 pathways, activates, expands, and differentiates any human T cells ex vivo, activates at concentration in the femtomolar range between about 10 to about 500 fM, such as about 170 fM, or promotes the preferential growth of human CD8+ T cells over the course of 12 days.
It is well established in the art that minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by the US Pat No 7,084,257.
The 7,084,257 patent (of record) teaches an isolated human monoclonal antibody comprising a heavy chain and a light chain wherein the reference light chain is at least 95.9% identical to the claimed SEQ ID NO: 144 and paired with any heavy chain and yet the reference human monoclonal antibody binds to human interferon gamma instead of an epitope LEEKKGNYVVTDHC (SEQ ID NO: 56) on EGFRvIII (see entire document, reference SEQ ID NO: 92, bottom sequence in alignment set forth below, in particular). There are no working examples. It is unpredictable which modification such as any substitution, deletion, addition or a combination thereof still maintains binding to human CD28 and human CD3, much less maintaining agonizing to both CD3 and CD28 pathways.
As such, it would require undue experimentation of one skilled in the art to practice the claimed invention commensurate in scope with the claims.
The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970).
Given the lack of any rebuttal to enablement rejection, the rejection is maintained for reasons of record.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-3, 9, 10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Kufer et al. (WO2004/106381, published 12/09/2004; PTO 892) in view of Pulé et al. (WO2016/139463, published 09/09/2016; PTO 892).
Claim 1. A bispecific scFv construct agonizing both CD3 and CD28 pathways, wherein the anti-CD28 scFv is at the N-terminus of the construct and the anti-CD3 scFv is at the C-terminus of the construct.
Claim 2. The construct of claim 1, wherein the construct is soluble.
Claim 3. The construct of claim 1 or 2, wherein the construct activates, expands, and differentiates human T cells ex vivo.
Claim 9. The construct of claim 1, comprising one or more flexible linkers.
Claim 10. The construct of claim 9, comprising a flexible linker between each heavy and light chain domain of each scFv as well as a flexible linker between each scFv.
Claim 12. The construct of claim 1, comprising a purification tag.
Regarding claims 1-2, Kufer teaches a bispecific single chain antibody construct, said bispecific single chain antibody construct comprising binding domains specific for human CD3 and human CD19, wherein the corresponding variable heavy chain regions (VH) and the corresponding variable light chain regions (VL) are arranged, from N-terminus to C-terminus, in the order, VH(CD19)-VL(CD19)-VH(CD3)-VL(CD3) wherein said scFv molecules are linked using a G4S1 linker, see entire document, p. 1, Figure 1, p. 5, p. 9, lines 22-25, and p. 25, lines 10-13. Kufer et al. also teach an anti-CD3 scFv (SEQ ID NO: 47). Kufer et al. teach that OKT3 or other anti-CD3 antibodies can be used as immunopotentiating agents to stimulate T cell activation and proliferation, see p. 3, in particular. The bispecific single chain Fv (scFv) are known in the art, see p. 9. The VH and VL regions of said CD3 specific domain are from any one of the CD3 specific antibody shown on p. 11, particularly OKT-3. The anti-CD3 scFv antibody recognizing human CD3 epsilon in the context of other TCR subunits, see p. 12. Kufer et al. teach that “[t]he pharmaceutical composition of the invention may also comprise a proteinaceous compound capable of providing an additional activation signal for immune effector cells. Such compounds may comprise, but are not limited to CD28 engagers…”, see p. 22, in particular.
Kufer does not teach the bispecific scFv construct agonizing both CD3 and CD28 pathway wherein the anti-CD28 scFv is at the N-terminus as per claim 1.
However, Pulé et al. teach a widely used approach to expand T cells is to add soluble mitogenic monoclonal antibodies (mAb) such as anti-CD3 and anti-CD28, to the cell culture, see p. 1, lines 16-17. Pulé et al. teach that OKT3 is an agonist anti-CD3 antibody that binds to human CD3 and comprises the amino acid sequence of SEQ ID NO: 1; TGN1412 is an anti-CD28 antibody that not only binds to, but is a strong agonist for CD28 (p. 19) and comprises the amino acid sequence of SEQ ID NO: 3, see p. 15 and 16. Pulé et al. teach SEQ ID NO: 3, which is a TGN1412 (anti-CD28) scFv that is a T cell activating protein.
Regarding claim 1, substituting Kufer’s CD19 specific VH and VL locate at the N-terminus in VH(CD19)-VL(CD19)-VH(CD3)-VL(CD3) for Pulé et al’s CD28 specific VH and VL would arrive at the claimed VH(CD28)-VL(CD28)-VH(CD3)-VL(CD3), in which anti-CD28 scFv is at the N-terminus of the construct and the anti-CD3 scFv at the C-terminus of the construct.
Claims 2 and 3 are included as Pulé et al. teach bispecific scFv mAb is soluble and widely used approach is to add soluble mitogenic monoclonal antibodies (mAb) such as anti-CD3 and anti-CD28, to the cell culture, see p. 1, lines 16-17.
Regarding claims 9-10, Kufer teaches that the bispecific construct comprises three flexible linkers, e.g., (G4S)2, a linker between each heavy and light chain domain of each scFv as well as a flexible linker between each scFv, see Fig. 1A, in particular.
Regarding claim 12, Pulé et al. teach the construct comprising a purification tag, e.g., GST-tag or GST domain, which is commonly used in molecular biology to enable the isolation of a GST-tagged protein from a protein mixture, see p. 26-27.
In view of the combined teachings of Kufer et al and Pulé et al, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to have made the claimed bispecific scFv antibody by substituting Kufer’s scFv that binds to human CD19 located at the N-terminus for Pulé’s anti-CD28 scFv to arrive at the claimed soluble bispecific scFv construct that agonizing both human CD28 and human CD3 pathway, activating, expanding and differentiating human T cells in cell culture (aka ex vivo).
One of ordinary skill in the art would have been motivated to do so, because Kufer teaches that anti-CD3 scFv antibody such as OKT3 can be used as immunopentiating agents to stimulate T cell activation and proliferation and anti-CD3-antibodies have also been used in combination with anti-CD28-antibodies to induce T cell proliferation (see p. 3, second paragraph) and Pulé et al. teaches that TGN1412 is an anti-CD28 antibody that not only binds to, but is a strong agonist for CD28 (p. 19) and the combination of anti-CD3 and anti-CD28 has been widely used to add to the cell culture for T cells activation, see p. 1, lines 16-17.
One of ordinary skill in the art would have been motivated with a reasonable expectation of success at the effective filing date of the invention to make bispecific scFv that binds to CD3 and CD28 because Kufer teaches the use of three flexible linkers to link between VH and VL domains and between each scFv to form a bispecific scFv that simultaneously engages CD3 and CD28 using Pulé’s VH and VL from TGN1412 and anti-CD3 scFv (OKT3) to delivering activation and co-stimulation in one molecule to T cells for expansion in vitro.
One of ordinary skill in the art would have been motivated to do so because the simplest ways to generate multifunctional agents is to genetically fuse two scFv domains with differing specificity using flexible G4S or (G4S)3 linkers, creating tandem scFvs using agonistic TGN1412 (anti-CD28 scFv) and anti-CD3 scFv (OKT3) of Pulé’s with similar properties as the parental scFv antibodies.
Further, “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Applicant’s arguments, filed August 7, 2026, have been fully considered but are not found persuasive.
Applicant’s position is that Independent claim 1 is directed to a bispecific scFv construct agonizing both CD3 and CD28 pathways, wherein the anti-CD28 scFv is at the N-terminus of the construct and the anti-CD3 scFv is at the C-terminus of the construct.
None of the cited references, alone or in combination, teach, suggest, or motivate the skilled person to arrive at a construct with anti-CD28 scFv and anti-CD3 scFv, in the claimed orientation.
In addition, none of the cited references teach or suggest the claimed dual agonism of the construct.
Kufer discloses CD3 activation and CD19 targeting. Not only are these not the same targets of the claimed construct, but there is absolutely no motivation in Kufer to substitute the anti-CD19 scFv in any of the construct formats of Kufer with the anti-CD28 scFv of the disclosure of Pule. Each of these references has different desired objectives and the constructs described therein achieve that goal. In this regard, Applicant notes that these molecules are different and have different functions and, thus, the skilled person would know that CD28 and CD19 are not analogous targets. For further emphasis, CD19 relates to B cells and B cell malignancies while CD28 relates to T cells. Thus, substituting one for the other would result in a construct that acts on completely different targets to produce a completely different functional outcome. Neither disclosure provides motivation for the skilled person to proceed in this manner.
Moreover, as construct design and geometry are also important considerations, one would not expect replacing CD19 with CD28 to yield predictable results. For at least the reasons provided herein, it is clear that the references fail to provide any motivation to modify the disclosures and any guidance or direction that would lead a person to the instantly claimed construct with a reasonable expectation of success. In the absence of any teaching or suggestion in the references to make such a substitution, let alone to motivate the skilled person to do so, the skilled person is not led to the claimed invention in view of the teachings of any of the cited references.
U.S. '962 fails to cure any of the above-noted deficiencies and therefore the independent claim submitted herewith is patentable in view of this reference, alone, or in combination with either Kufer or Pule, for at least the same reasons.
In response to applicant's argument that None of the cited references, alone or in combination, teach, suggest, or motivate the skilled person to arrive at a construct with anti-CD28 scFv and anti-CD3 scFv, in the claimed orientation, simple substitution of Kufer’s CD19 specific VH and VL which locate at the N-terminus in VH(CD19)-VL(CD19)-VH(CD3)-VL(CD3), for Pulé et al’s CD28 specific VH and VL would arrive at the claimed VH(CD28)-VL(CD28)-VH(CD3)-VL(CD3), would arrive at a construct with anti-CD28 scFv and anti-CD3 scFv, in the claimed orientation. The test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Further, choosing a bispecific scFv having anti-CD28 scFv fused to at the N-terminus or C-terminus of anti-CD3 scFv is considered a finite number of options for bispecific scFv constructs, with a reasonable expectation of success, see KSR International Co. V. Teleflex Inc. 82 USPQ2d 1385 (2007).
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. 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). Moreover, the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ1,5-6 (Fed. Cir. 1983). In addition, attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection.
In this case, those of skill in the art would have found it prima facie obvious to link the agonist scFv that binds to CD28 and activates T cells of Pulé et al (p. 19) to the N-terminus of Kuffer’s agonist scFv that binds to CD3 of Kuffer because Pulé et al. teach that adding anti-CD3 and anti-CD28 add to cell culture is a widely used approach to expand T cells (see p. 1, lines 16-17) and Kufer et al. teach that OKT3 or other anti-CD3 antibodies can be used as immunopotentiating agents to stimulate T cell activation and proliferation (see p. 3) and may also comprise, but are not limited to CD28 engagers…” (see p. 22). Thus, anyone of skill in the art would understand that the same agonist scFv antibody that binds to CD28 and the same agonist scFv that binds to CD3 in a bispecific scFv format can activate, expand, and differentiate human T cells in vitro.
Evidentiary reference WO2019236681 publication teaches anti-CD3 scFv on the surface of the beads can bind and activate T cells, while anti-CD28 scFv and 4-1BBL on the surface of the beads can provide dual co- stimulation for the T cells resulting in decreased levels of the markers CD25, TIM3, LAG3, and PD1. This is a less costly and more efficient alternative to peripheral blood mononuclear cells (PBMCs) and cytokine treatments that result in better quality T cell for adoptive transfer back into patients, see Summary, in particular. As such, "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, e.g., activating T cells, in order to form a third composition to be used for the very same purpose, e.g., stimulating and activating T cells... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205USPQ 1069, 1072 (CCPA 1980) (see MPEP 2144.06).
In this case, applying known technique of making bispecific scFv antibody of Kufer to a known product would ready for making bispecific scFv antibody in the same way.
A person of ordinary skill in the art is always motivated to pursue the known options within her or his technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
Obviousness is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR International Co. V. Teleflex Inc. 82 USPQ2d 1385 (2007). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
In response to applicant's argument that CD28 and CD19 are not analogous targets for the bispecific scFv antibody, “When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one (emphasis added). If a person of ordinary skill can implement a predictable variation, §103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill.” Clearly in the instant case the making bispecific scFv antibody that binds to CD28 and CD3 using known agonist VH and VL that binds to human CD28 and human CD3 would have been obvious at the time the invention was made. See KSR v Teleflex (500 US 298 2007), pages 12-13.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, 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, the teachings of Kufer pertaining to OKT3 or other anti-CD3 antibodies that can be used as immunopotentiating agents to stimulate T cell activation and proliferation and that bispecific scFv antibody can be made using said scFv for targeting and the teachings of Pulé et al pertaining to TGN1412 (anti-CD28) scFv that activates T cell and OKT3 is an agonist anti-CD3 antibody that binds to human CD3 and the combination of anti-CD3 and anti-CD28 has been widely used approach to expand T cells in the cell culture (see p. 1, lines 16-17) would have led one of ordinary skill in the art to make a bispecific scFv antibody that binds to human CD3 and human CD28 in the same way for T cell activation, expansion or recruitment.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time the invention was made especially in the absence of evidence to the contrary.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., construct design and geometry are also important considerations) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
For these reasons, the rejection is maintained.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Kufer et al. (WO 2004/106381, published 12/09/2004; PTO 892) in view of Pulé et al. (WO 2016/139463, published 09/09/2016; PTO 892) as applied to claims 1-3, 9, 10 and 12 mentioned above and further in view of US Patent No. 9,226,962 (issued January 5, 2016; PTO 892).
The teachings of Kufer and Pulé have been discussed supra.
The references do not teach that the construct comprising a histidine tag as per claim 13.
However, the ‘962 patent teaches anti-CD3 scFv construct comprising a His6 tag at the C-terminus of the scFv for both immunodetection and purification of recombinant product by immobilized metal-affinity chromatography (IMAC), see FIG. 2, Example 1, col. 10, lines 43-46, reference SEQ ID NO: 2, in particular.
In view of the combined teachings of Kufer et al, Pulé et al and the ‘962 patent, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to substitute the GST-tag in the bispecific scFv construct of Kufer et al, Pulé for the 6His tag of ‘962 patent to arrive at the claimed invention with a reasonable expectation of success, e.g., bispecific construct comprising a histidine tag at the C-terminus.
One of ordinary skill in the art would have been motivated to do so because the ‘962 patent teaches that the six histidine residues at the C-terminus of scFv is useful for both immunodetection and purification of recombinant product by immobilized metal-affinity chromatography (IMAC), see col. 10, line 43-46, in particular.
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Applicant’s arguments, filed August 7, 2026, have been fully considered but are not found persuasive.
Applicant’s position is that U.S. '962 fails to cure any of the above-noted deficiencies and therefore the independent claim submitted herewith is patentable in view of this reference, alone, or in combination with either Kufer or Pule, for at least the same reasons.
In response, the arguments with respect to the primary references Kufer et al. (WO 2004/106381, published 12/09/2004; PTO 892) and Pulé et al have been discussed supra and incorporated here by reference.
Kufer and Pulé do not teach that the construct comprising a histidine tag as per claim 13.
However, the ‘962 patent teaches anti-CD3 scFv construct comprising a His6 tag at the C-terminus of the scFv for both immunodetection and purification of recombinant product by immobilized metal-affinity chromatography (IMAC), see FIG. 2, Example 1, col. 10, lines 43-46, reference SEQ ID NO: 2, in particular.
In view of the combined teachings of Kufer et al, Pulé et al and the ‘962 patent, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to substitute the GST-tag in the bispecific scFv construct of Kufer et al, Pulé for the 6His tag of ‘962 patent to arrive at the claimed invention with a reasonable expectation of success, e.g., bispecific construct comprising a histidine tag at the C-terminus.
One of ordinary skill in the art would have been motivated to do so because the ‘962 patent teaches that the six histidine residues at the C-terminus of scFv is useful for both immunodetection and purification of recombinant product by immobilized metal-affinity chromatography (IMAC), see col. 10, line 43-46, in particular.
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
For these reasons, the rejection is maintained.
Conclusion
Claim 16 is 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.
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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