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, 6-7 and 9-17 are pending.
Claims 1, 6-7 and 9-17, drawn to an antibody-drug, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 62/902,674, filed September 19, 2019, is acknowledged.
Claim Objection
Claim 7 is objected to because of the following informality: “linker” is missing after “cleavable”.
Rejection Withdrawn
Upon reconsideration, the enablement rejection of claims 1, 6, 9, and 11-17 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph is withdrawn in view of one of ordinary skill in the art can make and use the antibody-drug conjugate at the time of filing.
The rejection of claims 1, 6 and 11-15 under 35 U.S.C. 103 as being unpatentable over US 20180169261 (Sutherland hereafter, published June 21, 2018; PTO 1449) in view of Ivanyi et al (Cellular Oncology 32: 101-108, 2010; PTO 1449) and Haber et al (newly cited, US20180118848, published May 3, 2018; PTO 892) is withdrawn in favor of new ground of rejection.
The rejection of claim 9 under 35 U.S.C. 103 as being unpatentable over US20180169261 (Sutherland hereafter, published June 21, 2018; PTO 1449) in view of Ivanyi et al (Cellular Oncology 32: 101-108, 2010; PTO 1449) and Haber et al (newly cited, US20180118848, published May 3, 2018; PTO 892) as applied to claims 1, 6 and 11-15 mentioned above and further in view of WO2016160615 publication (published Oct 6, 2016; PTO 1449) is withdrawn in favor of new ground of rejection.
The rejection of claim 1 under 35 U.S.C. 103 as being unpatentable over US20180169261 (Sutherland hereafter, published June 21, 2018; PTO 1449) in view of Ivanyi et al (Cellular Oncology 32: 101-108, 2010; PTO 1449) and Haber et al (newly cited, US20180118848, published May 3, 2018; PTO 892) as applied to claims 6 and 11-15 mentioned above and further in view of US20180134794 (Babb hereafter, published May 17, 2018; PTO 1449) is withdrawn in favor of new ground of rejection.
The rejection of claims 16 and 17 under 35 U.S.C. 103 as being unpatentable over US20180169261 (of record, Sutherland hereafter, published June 21, 2018; PTO 1449) in view of Ivanyi et al (of record, Cellular Oncology 32: 101-108, 2010; PTO 1449) and Haber et al (newly cited, US20180118848, published May 3, 2018; PTO 892) as applied to claims 1, 6 and 11-15 mentioned above and further in view of Boshuizen (of record, US20180326084, published November 15, 2018; PTO 892) is withdrawn in favor of new ground of rejection.
Claim rejections under - 35 U.S.C. 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6-7 and 9-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The 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: the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
For claims drawn to a genus, 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, See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406, M.P.E.P. § 2163, II, A, 3, (a), (ii).
Claim 1 encompasses an antibody-drug conjugate (ADC) comprising any antibody or antigen- binding fragment thereof that specifically binds human pre-T cell antigen receptor alpha (PTCRA), wherein the antibody or antigen-binding fragment thereof is conjugated to a therapeutic moiety through a linker, wherein the therapeutic moiety is selected from the group consisting of monomethyl auristatin E (MMAE), maytansine
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Claim 6 encompasses the ADC of claim 1, wherein the antibody or antigen-binding fragment thereof is conjugated to the therapeutic moiety through a non-cleavable linker.
Claim 7 encompasses the ADC of claim 1, wherein the antibody or antigen-binding fragment thereof is conjugated to the therapeutic moiety through an enzyme-labile cleavable linker once the ADC is administered to a patient in need thereof.
Claim 9 encompasses the ADC of claim 1, wherein the linker is bonded to a lysine residue of the antibody or antigen-binding fragment thereof.
Claim 10 encompasses the ADC of claim 1, wherein the antibody or antigen-binding fragment thereof is conjugated to the therapeutic moiety through a linker, wherein the linker is bonded to a cysteine residue of the antibody or antigen-binding fragment thereof.
Claim 11 encompasses the ADC of claim 1, wherein the ADC kills cells that express human PTCRA.
Claim 12 encompasses the ADC of claim 1, wherein the ADC kills human T-cell acute lymphoblastic leukemia (T-ALL) cells.
Claim 13 encompasses a pharmaceutical composition comprising the ADC of claim 1 and one or more pharmaceutically acceptable carriers, diluents, or excipients.
Claim 14 encompasses the pharmaceutical composition of claim 13, wherein the composition is useful for inhibiting or reducing tumor growth in a tumor-bearing subject, wherein tumors of the subject over-express pre-T cell antigen receptor alpha (PTCRA).
Claim 15 encompasses the pharmaceutical composition of claim 13, wherein the composition is useful for treating T-cell acute lymphoblastic leukemia (T-ALL) in a subject, wherein tumors of the subject over-express pre-T cell antigen receptor alpha (PTCRA).
Claim 16 encompasses a kit comprising the ADC of claim 1 and instructions for use.
Claim 17 encompasses a kit comprising the pharmaceutical composition of claim 13 and instructions for use.
Regarding antibody and antigen-binding fragment thereof, the specification discloses:
[0040] The term "antibody", as used herein, also includes antigen-binding fragments of full antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.
[0041] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment," as used herein.
[0046] In certain embodiments, the anti-PTCRA antibodies of the ADCs are human antibodies. The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the ADCs of the disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
[0047] The antibodies of the ADCs of the disclosure may, in some embodiments, be recombinant human antibodies. The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the V.sub.H and V.sub.L regions of the recombinant antibodies are sequences that, while derived from and related to human germline V.sub.H and V.sub.L sequences, may not naturally exist within the human antibody germline repertoire in vivo.
[0088] The present disclosure, according to certain embodiments, provides antibody-drug conjugates comprising anti-PTCRA antibodies that bind to human PTCRA, but not to PTCRA from other species. The present disclosure also includes antibody-drug conjugates comprising anti-PTCRA antibodies that bind to human PTCRA and to PTCRA from one or more non-human species. For example, the ADCs disclosed herein may comprise anti-PTCRA antibodies that bind to human PTCRA and may bind or not bind, as the case may be, to one or more of mouse, rat, guinea pig, hamster, gerbil, pig, cat, dog, rabbit, goat, sheep, cow, horse, camel, cynomolgus, marmoset, rhesus or chimpanzee PTCRA. According to certain exemplary embodiments, the ADCs disclosed herein may comprise anti-PTCRA antibodies that specifically bind human PTCRA and cynomolgus monkey (e.g., Macaca fascicularis) PTCRA. Other ADCs disclosed herein may comprise anti-PTCRA antibodies that bind human PTCRA but do not bind, or bind only weakly, to cynomolgus monkey PTCRA.
The specification discloses pre-T cell antigen receptor alpha (PTCHA) is expressed in human T-cell acute lymphoblastic leukemia (T-ALL), see Examples 4-6. The specification exemplifies PTCRA-targeting mouse mAb or an isotype control mAb conjugated to monomethyl auristatin E (MMAE) via a non-cleavable linker or a potent microtubule inhibitor (MAYT2) via a non-cleavable linker. To this end, the PTCRA-targeting mAb was conjugated to MAYT2INT. The resulting drug-antibody ratio (DAR) was .about.3.5, and the compound was hereafter referred to as PTCRA-ADC. The PTCRA-ADC, but not a control-ADC, promoted dose-dependent killing of leukemic cells with an IC50 in the low nanomolar range (FIG. 16B, tabular form of values shown in FIG. 16F, Example 7. The specification discloses synthesis of additional linker payloads formats would also have anti-leukemic activity. To this end, the PTCRA-targeting mAb was conjugated to additional linker payload MAYT3LP (structure provided herein), thereby linking the PTCRA-targeting mAb to the potent microtubule inhibitor (MAYT3) via a non-cleavable linker. Toward this end, the PTCRA-targeting mAb was reacted with MAYT3LPINT. The resulting drug-antibody ratio (DAR) was .about.3.5, and the compound is hereafter referred to as PTCRA-MAYT3LP. Additionally, the PTCRA-targeting mAb was conjugated to additional linker payload MAYT4LP (structure provided herein), thereby linking the PTCRA-targeting mAb to the potent microtubule inhibitor (MAYT4) via a cleavable linker. To this end, the PTCRA-targeting mAb was reacted with compound 14 described in Example 8. The resulting drug-antibody ratio (DAR) was .about.3.5, and the compound is hereafter referred to as PTCRA-MAYT4LP. The ADCs PTCRA-MAYT3LP and PTCRA-MAYT4LP, but not the appropriate control-ADCs, promoted dose-dependent killing of human PTCRA+ leukemic cells with an IC50 in the low nanomolar range (FIG. 19A, tabular form of values shown in FIG. 19G). The activity of PTCRA-MAYT3LP and PTCRA-MAYT4LP was tested on a panel of human leukemia cell lines. The PTCRA-ADC selectively induced killing of human SupT1 T-ALL cells, but did not impact viability of B-ALL (NALM6) and AML (K562) cell lines (FIG. 19B, tabular form of values shown in FIG. 19H). AML and B-ALL cells have very low levels of PTCRA at the RNA level (median and mean approaching <1 for most datasets). Furthermore, PTCRA-MAYT3LP and PTCRA-MAYT4LP treatment also had no effect on the viability of normal, peripheral T cells, consistent with its selective expression pattern. The in vitro efficacy of these molecules prompted the evaluation of their anti-leukemic activity in various in vivo models of T-ALL. To this end, NSG mice were injected subcutaneously (s.c.) with 5,000,000 PTCRA+ SupT1 cells and randomized to treatment with either a single dose of PTCRA-MAYT4LP or the Control-MAYT4LP, once the tumors became palpable. Tumor burden was quantified longitudinally throughout the study by measuring the tumor volume of the implanted tumor. T-ALL-bearing mice treated with the PTCRA-MAYT4LP exhibited statistically significantly reduced tumor burden relative to Control-2921 treated mice (FIG. 19C). In a separate experiment, C57BL/6 mice were intravenously (i.v.) injected with PTCRA+ mTALL cells and randomized according to tumor burden on day 1 post implantation and treated with either PTCRA-MAYT4LP or Control-2921 2qw. Tumor burden was assessed longitudinally throughout the study by quantifying the number of blast cells in the peripheral blood and by quantifying splenic mass at the end of study at day 21. T-ALL-bearing mice treated with the PTCRA-MAYT4LP exhibited statistically significantly reduced tumor burden, both in peripheral blood and spleen relative to Control-2921 controls (FIG. 19D and FIG. 19E). PTCRA-MAYT4LP treatment also was not associated with T-cell aplasia, highlighting the specificity of PTCRA-targeting molecules for leukemic T-cells versus non-malignant T-cells (FIG. 19F).
However, the disclosure of just one anti-mPTCRA (2F5, see para. [00163]) that binds to mouse and human PTCRA is not representative of genus. The specification does not describe any relevant, identifying characteristics, such as structure, e.g., amino acid sequences of the heavy and light chain variable regions or the six CDRs that correlated with binding to human pre-T cell antigen receptor alpha (PTCRA) or structure common to members of the genus of antibody wherein the antibody or antigen-binding fragment thereof conjugated to MMAE or DM1 through any linker, sufficient to show possession of the claimed genus. Thus, one of skill in the art cannot "visualize or recognize" most members of the genus of antibody-drug conjugate (ADC).
It is 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. Protein Engineering, Design & Selection 22:159-168, 2009; see, e.g., Discussion).
Similarly, Edwards et al., J Mol Biol. 334(1): 103-118, Nov 14, 2003, 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).
Poosarla et al (of record, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
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).
A “patentee of a biotechnological invention cannot necessarily claim a genus after only describing one 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 Biochem II, 323 F. 3d at 965; Regents, 119 F.3d at 1568), MPEP 2163.IIAii
Section 112 states that “[t]he specification shall contain a written description of the invention . . . in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains . . . to make and use the same . . . .” This requirement ensures “that the inventor actually invented the invention claimed.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc). To show invention, a patentee must convey in its disclosure that it “had possession of the claimed subject matter as of the filing date.” Id. at 1350. Demonstrating possession “requires a precise definition” of the invention. Id. To provide this “precise definition” for a claim to a genus, a patentee must disclose “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.
When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. A description of what a material does, rather than of what it is, usually does not suffice. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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 all IL-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.
In Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), the court explained in Amgen that when an antibody is claimed, 35 U.S.C § 112(a) requires adequate written description of the antibody itself. 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).
In this case, the structure, e.g., amino acid sequences of the heavy and light chain variable domains or the six CDRs of the genus of antibodies that bind to human pre-T cell antigen receptor alpha (PTCRA) encompassed by the claimed antibody-drug conjugates are not described.
It is unpredictable which undisclosed antibody conjugated to MMAE or DM1 via a linker is effective for treating T-cell acute lymphoblastic leukemia (T-ALL) in all subject. Thus, without further written description of the antibody or antigen binding fragment thereof encompassed by the claimed antibody-Drug conjugate, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed antibody-drug conjugate (ADC) at the time of filing.
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.
In light of the number of representative number of species provided and the lack of structural features common to the members of the genus of antibody or antigen-binding fragment thereof that specifically binds human pre-T cell antigen receptor alpha (PTCRA) encompassed by the claimed antibody-drug conjugates, one skilled in the art would not recognize that applicant was in possession of the genus of antibody-drug conjugates for inhibiting or reducing any tumor growth in any tumor-bearing subject (claim 14), such as any hematopoietic tumor or treating T-cell acute lymphoblastic leukemia (T-ALL) in any subject over-express pre-T cell antigen receptor alpha (PTCRA, claim 15) that meets the written description provision of 35 U.S.C. § 112, first paragraph at the time of filing.
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 July 21, 2025 have been fully considered but they are not persuasive.
Applicant states that Independent claim 1 is directed to an antibody-drug conjugate (ADC) wherein the antibody or antigen-binding fragment thereof specifically binds cells expressing human pre-T cell antigen receptor alpha (PTCRA) and wherein the therapeutic moiety is selected from the group consisting of only six compounds specifically defined by the recited structures.
As an initial matter, the Office Action dated January 3, 2025 specifically stated that the now pending claims satisfied the written description requirement. (Office Action (1/3/2025) at p. 14 (top paragraph).) It appears this current office action may have been issued in error. Regardless, the currently pending claims comply with the written description requirement for at least the following reasons.
Antibody-drug conjugates (ADC) as an anti-cancer approach comprise a monoclonal antibody conjugated (via a linker) to a cytotoxic payload, wherein the antibody allows binding to a target antigen expressed on the cancer cell surface, which reduces systemic exposure/toxicity (exposure/toxicity for non-targeted/unbound cells). The selection of an appropriate target (unique antigenic target bound by antibody) thus constitutes one key determinant of the safety and efficacy of an ADC.
The antibody of the antibody-drug-conjugate (ADC) according to the claimed compositions is an antibody or antigen-binding fragment thereof that specifically binds human pre-T cell antigen receptor alpha (PTCRA). Indeed, per the application as filed, the antibody of the antibody-drug-conjugate claimed compositions targets PTCRA (the unique antigen). The antibody's specific binding (targeting) capacity allows the ADC to deliver its payload (toxin) to PTCRA expressed by tumors, to PTCRA expressed on T-ALL cells, and to PTCRA expressed on cells. Thus, the antibody's function in the ADC administered according to the claimed methods is fulfilled via its ability to specifically bind PTCRA, and the antibody itself does not require further definition (exact CDR sequences or the like).
Furthermore, normal peripheral T-cells do not express PTCRA. The antibody's binding/targeting function spares T cells that do not express PTCRA from the cytotoxic action of the payload linked to the antibody of the ADC of the claims ([00131] and [00132] of application as filed).
The antibody's targeting ability is exemplified in the application as filed. As referred to by the Examiner, in Example 7, the PTCRA-ADC, but not a control-ADC, promoted dose-dependent killing of leukemic cells. The antibody of the ADC is limited to an antibody or antigen-binding fragment thereof that specifically binds human pre-T cell antigen receptor alpha (PTCRA); if the antibody cannot bind/target PTCRA, the ADC of the claims cannot target the tumors, T-ALL cells, and cells expressing PTCRA. Furthermore, the antibody's non-binding of normal peripheral T cells is exemplified in the application as filed (Examples 4 and 5). Thus, Applicant submits that the ordinarily skilled artisan could recognize a member of the genus of ADCs according to the claims.
In response, the amendment to claim 1 is acknowledged.
Claim 1 encompasses any antibody-drug conjugate (ADC) comprising an antibody or antigen- binding fragment thereof that specifically binds human pre-T cell antigen receptor alpha (PTCRA), wherein the antibody or antigen-binding fragment thereof is conjugated to a therapeutic moiety through an optional linker, wherein the therapeutic moiety is selected from the group consisting of monomethyl auristatin E (MMAE), maytansine
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Upon reconsideration, the claims do not meet the written description requirement because of the following reasons.
Regarding antibody and antigen-binding fragment thereof, the specification defines antibody as follow:
[0040] The term "antibody", as used herein, also includes antigen-binding fragments of full antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.
[0041] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment," as used herein.
[0046] In certain embodiments, the anti-PTCRA antibodies of the ADCs are human antibodies. The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the ADCs of the disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
Thus, the antibody that binds to human pre-T cell antigen receptor is unlimited. The specification exemplifies just one monoclonal antibody.
The specification discloses just one anti-mPTCRA (2F5, see para. [00163]) that binds to mouse and human PTCRA is not representative of genus. The specification exemplifies:
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However, the specification does not describe the structure-identifying information, e.g., the amino acid sequences of the heavy and light chain variable domain of antibody or antigen-binding fragment thereof that bind to any epitope of human pre-T cell antigen receptor alpha (PTCRA), nor describe a representative number of species falling within the scope of the genus or structural common to the members of the genus of antibody encompassed by the claimed ADC so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed antibody-drug conjugate (ADC) themselves. The definition by function alone, e.g., binds to human pre-T cell antigen receptor alpha (PTCRA) is not sufficient to define the genus because it is only an indication of what the antibody does, rather than what it is.
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.
Further, “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.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
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.").
It is 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. 334(1): 103-118, 2003; 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).
Poosarla et al (of record, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
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 or epitope of an 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).
Further, considering an antibody will have six CDRs, each CDR comprising approximately ten amino acid residues. With twenty naturally occurring amino acids, the potential size of the CDR variation, of just human antibodies within this indeterminate genus, is 2060. This does not include the potential variation within the framework regions of the heavy and light chain variable domain for the first domain that binds to any epitope of human pre-T cell antigen receptor alpha (PTCRA).
Given the genus of antibodies is unknown, both in terms of size and structural diversity, and neither applicant’s specification nor the knowledge in the art, allows the skilled artisan to predict the undisclosed members of the genus, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of the antibody or antigen-binding fragment thereof that binds to any epitope of human pre-T cell antigen receptor alpha (PTCRA) encompassed by the claimed antibody-drug conjugate (ADC). One of skill in the art would conclude that the specification fails to disclose a representative number of species of antibody or antigen binding fragment thereof that binds to human pre-T cell antigen receptor alpha (PTCRA) encompassed by the claimed antibody-drug conjugate (ADC).
Therefore, there is insufficient written description for genus of antibody-drug conjugate (ADC) broadly encompassed by the claimed invention to provide sufficient structure for the antibody or antigen-binding fragment thereof that binds any epitope of human pre-T cell antigen receptor alpha (PTCRA) claimed at the time the invention was made and as disclosed in the specification as filed under the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
For these reasons, the rejection is maintained.
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 of this title, 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 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 1, 7 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Doronina et al (Bioconjugate Chem 17: 114-124, 2006; PTO 892) in view of Garcia (WO03/016355, published February 27, 2003; PTO 892), Ivanyi et al (of record, Cellular Oncology 32: 101-108, 2010; PTO 1449) and Bellavia et al (Pro. Natl. Acad. 99: 3788-3793, 2002; PTO 892).
Regarding claim 1, 7, 10, Doronina teaches antibody-drug conjugates (ADCs) comprising cAC10 (anti-CD30) linked to monomethylauristatin E (MMAE) through a linker such as maleimidocaproyl-valine-citrulline-paminobenzyloxycarbonyl, see entire document, abstract, p. 115, in particular.
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This is comprised of the highly potent antimitotic agent MMAE, attached to mAb-cysteines through the L1 linker that is cleaved by intracellular proteases such as cathepsin B, see p. 115. The ADC is able to binds to CD30 expressing cancer cell and killing CD30 expressing cancer cells, see p. 120, Figure 2C and D. Doronina teaches that mAb-maleimidocaproyl-valine-citrullinep-aminobenzyloxycarbonyl-MMAF (mAb-L1-MMAF) conjugates were >2200-fold more potent than free MMAF on a large panel of CD30 positive hematologic cell lines, see abstract, in particular.
Likewise, Ducry teaches antibody-drug conjugate (ADC) comprising mAb linker to a toxin payload, see Figure1, in particular. The antibody-drug conjugate comprising e.g., cAC10 (anti-CD30 monoclonal antibody) conjugated to a therapeutic agent, e.g., monomethyl auristatin E, through an enzyme cleavable linker such as valine-citrulline and p-aminobenzyloxycarbonyl (PABC) wherein the linker is linked to a cysteine (S) on the antibody, see p. 7, p. 8, Enzyme labile linker, in particular.
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Doronina and Ducry do not teach the antibody binds cells expressing human pre-T cell antigen receptor alpha (PTCRA) as per claims 1, wherein the ADC kills cells that express human PTCRA as per claim 11 or kill human T-cell acute lymphoblastic leukemia (T-ALL) cells as per claim 12.
However, Garcia teaches monoclonal antibody K5G3 that binds to human T cells that expressed pre T cell antigen receptor (aka pTα), see abstract, in particular.
Likewise, Ivanyi teaches Pre T-cell receptor alpha (aka pTα or PTCRA) expressed in human T-cell lymphoblastic leukemia cell lines using monoclonal antibody 2F5, see entire document, p. 102-103, Fig 1D, in particular. Maximum pTα expression was found prior to the β-selection in immature T-ALLs. Furthermore, pTαa was still expressed in mature T-ALLs, while pTαb was rarely detected, see p. 103, right col.
Bellavia teaches that deletion of pre-TCRalpha (pTα) in Notch3 transgenic mice inhibits tumor development, indicating a crucial role for pTα in T cell leukemogenesis. In human, acute lymphoblastic leukemias (ALL) in remission have lower transcript levels of Notch 3, HES-1 and pre-TCR alpha and pre-TCR b transcripts, whereas the expression of all these genes was dramatically reduced or absent in remission, see entire document, abstract, p. 3791, Fig. 4, in particular.
In view of the combined teachings of references, 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 by substituting the anti-CD30 antibody in the mAb-L1-MMAF ADC of Doronina or Ducry for another antibody, e.g., K5G3 monoclonal pTα of Garcia or 2F5 monoclonal pTα antibody of Ivanyi since Bellavia teaches that pTα plays a crucial role in leukemogenesis to arrive at the claimed invention with a reasonable expectation of success., e.g., targeting MMAF to human T-ALL that expressed Pre T-cell receptor alpha PTCRA (pTα) for killing of cancer cells.
The claims would have been obvious because the substitution of one known element, i.e., anti-CD30 antibody cAc10) for another (i.e., anti-pTα) would have yielded predictable results (e.g., minimize systemic toxicity of MMAE) to one of ordinary skill in the art at the time of the invention. In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
The person of ordinary skill would have had a reasonable expectation of success in doing so because the teachings of Doronina and Ducry pertaining to the success of targeting toxin MMAE using antibody and self-immolative linker to release the toxin to tumor cells, the teachings of Garcia and Ivanyi pertaining to antibody that binds to human pre-TCR alpha (aka pTα) and that pTα is expressed in subpopulations of T-ALL such as immature T-ALL and mature T-ALL and Bellavia’ s teaching pertaining to pTα play a crucial role in T cell leukemogenesis would have led one of ordinary skill in the art to substitute a known antibody for another to arrive at the claimed invention with a reasonable expectation of success, e.g., targeting MMAE to PTCRA expressing T-ALL while reduced systemic toxicity.
In this case, applying known technique of Doronina and Ducry conjugating a known antibody of Gracia or Ivanyi to MMAE via val-cit-PABC linker ready for improved the antibody-drug conjugate the same way with predictable results.
“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 fami