DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of the claims
Claims 1-8 are pending and are currently examined.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-8 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 claims
contain 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 inventors, at the time the application was filed, had possession of the
claimed invention.
"[T]he purpose of the written description requirement is to 'ensure that the scope of the
right to exclude, as set forth in the claims, does not overreach the scope of the inventor's
contribution to the field of art as described in the patent specification."' Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), "[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNFα with A2 specificity, can result in a claim that does not meet written description even if the human TNF-a protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011 ).
"[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." Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69).
A "representative number of species" means that those species that are adequately
described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) ("The '128 and '485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9.
Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the 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 to provide a "representative number'' of species.
The "structural features common to the members of the genus" needed for one of
skill in the art to 'visualize or recognize' the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875 ("[T]he application only provides amino acid sequence information (a molecular description of the antibody) for a single mouse variable region, i.e., the variable region that the mouse A2 antibody and the chimeric antibody have in common. However, the mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims."). A chimeric antibody shares the full heavy and light chain variable regions with the corresponding mouse antibody; that is, the structure shared between a mouse and chimeric antibody would generally be expected to conserve the antigen binding activity. Lastly, even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited
functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 ("The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.")
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad
Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show
invention, a patentee must convey in its disclosure that is "had possession of the claimed subject matter as of the filing date. Demonstrating possession "requires a precise definition" of the invention. To provide this precise definition" for a claim to a genus, a patentee must disclose "a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus" (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the
invention, i.e., to enable it (see Amgen at page 1361).
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 ).
In the instant case, the specification discloses specific monoclonal antibodies M24, M69 and their respective conjugates with doxorubicin (DOX) and auristatin (MMAE). Also the specification provides guidance and experimental data regarding cytotoxicity of M24- DOX toward multiple myeloma cells ([0175]) and cytotoxicity of M69-MMAE toward tumor cells such as Triple negative breast cancer (TNBC) (MDA-MB-468, MDA-MB-231 and BT549), prostate (DU145 and PC3), pancreas (PANC1 and MiaPaca1 ), non-small cell lung (NSCL) (H322 and H1299), Ovary (OVCARS), stomach (AGS), and Mantle cells lymphoma. However, the claims broadly encompass any monoclonal antibody conjugates that binds a complex between activated matriptase and its inhibitor HAl-1 and treat all malignancies. The present claims attempt to claim every immunoconjugate monoclonal antibody that binds a complex between activated matriptase, wherein the instant specification does not describe representative examples to support the full scope of the claims because the instant specification discloses only a few exemplary monoclonal antibody immunoconjugates. In contrast to Applicant's disclosure of the specific antibodies such as the immunoconjugates formed with the monoclonal antibodies M24 and M69, the instant disclosure, including the claims fail to disclose a representative number of species falling with 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.
A "representative number of species" means that those species that are
adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
Thus, when there is substantial variation within the genus, one must describe a
sufficient variety of species to reflect the variation within the genus. The "structural
features common to the members of the genus" needed for one of skill in the art to
'visualize or recognize' the members of the genus takes into account the state of the art
at the time of the invention. For example, the Federal Circuit has found that possession
of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011 ).
Here, the claims are directed to a genus of antigen-binding immunoglobulin molecules
are defined by their desired binding to an antigen and function of such binding.
It is well-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 over 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 (Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Given the well-known high level of polymorphism of immunoglobulins / antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; 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 genera of every monoclonal antibody immunoconjugate that binds a complex between activated matriptase and its inhibitor HAl-1 and treat all malignancies.
One of skill in the art would conclude that the specification fails to disclose a
representative number of species to describe the claimed genera.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claim(s) 1 and 3 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Dickson et al. (U.S. Patent 7,355,015- cited by Applicant).
Dickson et al. teach a method of detecting a malignancy or a pre-malignant lesion in breast or other tissue, or a pathologic condition, by detecting the presence of single chain or two-chain forms of matriptase in the tissue (abstract). They developed the monoclonal antibody M69 which recognizes the active form of matriptase (example 5). They also made immunoconjugates containing radioisotopes which are covalently (by the nature of the conjugation process) linked to the M69 (col. 25, lines 42-54). The antibodies may also be chemically modified by covalent conjugation to polymers and used in composition comprising various agents dictated by the route of administration (col. 22, line 36 to col 24, line 59).
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 2 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dickson et al. (cited above) in view of Doronina et al. (Nat. Biotech., 21, 778-784, 2003-
cited by Applicant).
The claim is drawn to an immunoconjugate selectively targeting cancer cells that express matriptase, comprising a matriptase antibody or antigen-binding fragment thereof, and a cytotoxic agent, wherein said cytotoxic agent is auristatin and the antibody binds a complex between activated matriptase and its inhibitor HAl-1.
The teachings of Dickson et al. were presented supra and they were silent about the conjugation with auristatin or Doxorubicin.
In the art at the time that the invention was made antibodies were extremely valued for targeting payloads to the cells that needed to be selectively eliminated by a toxin. For instance Doronina et al. teaches monoclonal antibody (mAb)-drug conjugates consisting of auristatin E (AE) and monomethylauristatin E (MMAE), linked to the chimeric mAbs cBR96 (specific to Lewis Y on carcinomas) and cAC10 (specific to CD30 on hematological malignancies). In vivo studies demonstrated that the peptide linked
conjugates induced regressions and cures of established tumor xenografts with therapeutic indices as high as 60-fold. These conjugates illustrate the importance of linker technology, drug potency and conjugation methodology in developing safe and efficacious mAb-drug conjugates for cancer therapy (abstract).
It would have been obvious for a person of ordinary skill in the art at the time that
the invention was made to have used the antibodies of Dickson et al. and covalently conjugate them to auristatin and obtain a potent tool for targeting matriptase expressing cancer cells with a reasonable expectation of success. This is because Doronina et al. successfully use auristatin for targeting antibodies. The motivation to do so would have been readily present for a skilled artisan because the drug conjugate would have been more selective in killing the cancer cells.
Claim 2 is rejected under pre-A IA 35 U.S.C. 103(a) as being unpatentable over
Dickson et al. (cited above) in view of Sivam G. (WO96/391183- cited by Applicant ).
The claim is drawn to an immunoconjugate selectively targeting cancer cells that
express matriptase, comprising a matriptase antibody or antigen-binding fragment thereof, and a cytotoxic agent, wherein said cytotoxic agent is auristatin and the antibody binds a complex between activated matriptase and its inhibitor HAl-1.
The teachings of Dickson et al. were presented supra and they were silent about the conjugation with Doxorubicin.
Sivam G. teaches compositions and methods for selective delivery of therapeutic
and diagnostic agents (effector molecules) to a target site or tissue in a host. The compositions are conjugates of effector molecules and targeting molecules, in which the
targeting molecule is directed to a binding site on the target cell, tissue, etc. The conjugate is formed by covalent attachment of the targeting molecule to an imine functionality which is present in, or generated in an effector moiety. The targeting molecule is covalently attached to the effector moiety (or derivatized moiety) at two or more positions (p.4, lines 10-25). The immunoconjugates are particularly useful in the treatment of tumors, where, for example, antibody-doxorubicin conjugates are effective against doxorubicin resistant tumor cells (abstract).
It would have been obvious for a person of ordinary skill in the art at the time that
the invention was made to have used the teachings of Sivam to obtain anti-matriptase
immunoconjugates for treating cancers that expressed matriptase as taught by Dickson
et al. with an excellent expectation of success since the method was widely known in the art as exemplified by Sivam .The motivation to do so is given by Sivam, which use their immunoconjugates for specific and targeted treatment of doxorubicin resistant cells, which would thus intracellularly integrate the doxorubicin and avoid drug resistance.
Claims 1-8 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable
over Dickson et al. (cited above) in view of Foltz et al. (U.S. Pub. No. 2006/0171884- cited by Applicant) and Sivam G. (WO96/391183).
The claims are drawn to an immunoconjugate comprising a chimeric, humanized
antibody, or human antibody or antigen binding fragment thereof that binds matriptase in a form selectively expressed on cancer cells; the antibody binds a complex between activated matriptase and its inhibitor HAl-1 and is further linked to a chemotherapeutic
agent. The chemotherapeutic agent may be doxorubicin or an auristatin. Also claimed is
a method to treat a malignancy in a subject by administering to a subject an effective
amount of the immunoconjugate. the malignancy is cancer of the breast, prostate, kidney, lung, colon, pancreas, skin, thyroid, ovary or stomach, or a hematological malignancy such as a B-cell lymphoma, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMOL)), Hodgkin's lymphomas, Non-Hodgkin's lymphomas, Burkitt's lymphoma (BL), diffuse large B-cell lymphoma (DLBL), Mantle cell lymphoma (MCL), or multiple myeloma.
The teachings of Dickson were presented supra and they were silent about treating malignancies with their antibody.
Foltz et al. teach fully human monoclonal antibodies and fragments thereof
directed to Matriptase. Some antibodies described are advantageous in that they provide a higher affinity towards Matriptase, in addition to a higher potency, than previously described anti-Matriptase antibodies. Further, unlike antibodies prepared by other means, embodiments of the invention include antibodies that have a very low, or non-measurable, immunogenicity in humans (abstract, [0010]). Also described are compositions, including an antibody or functional fragment thereof, and a pharmaceutically acceptable carrier to be used as therapeutic agents for the treatment of neoplastic diseases such as melanoma, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, thyroid tumor, gastric (stomach) cancer, prostate cancer, breast cancer, ovarian cancer, bladder cancer, lung cancer, glioblastoma, endometrial cancer, kidney cancer, colon cancer, pancreatic cancer, lymphoma including Burkitt's lymphoma, Non-Hodgkin's lymphoma, B-cell lymphoma, T-cell lymphoma and leukemia ([0015]-[0017]). A prostate cancer cell line showed expression of both Matriptase and HAl-1 ([0226]). The anti-Matriptase antibody, or a fragment thereof, is conjugated to a therapeutic agent that can be, for example, a toxin or a radioisotope ([0028]).
Sivam G. teaches compositions and methods for selective delivery of therapeutic
and diagnostic agents (effector molecules) to a target site or tissue in a host. The compositions are conjugates of effector molecules and targeting molecules, in which the targeting molecule is directed to a binding site on the target cell, tissue, etc. The conjugate is formed by covalent attachment of the targeting molecule to an imine functionality which is present in, or generated in an effector moiety. The targeting molecule is covalently attached to the effector moiety (or derivatized moiety) at two or more positions (p.4, lines 10-25). The immunoconjugates are particularly useful in the treatment of tumors, where, for example, antibody-doxorubicin conjugates are effective against doxorubicin resistant tumor cells (abstract).
It would have been obvious for a person of ordinary skill in the art at the time that
the invention was made to try antibody of Dickson et al. which bind both Matriptase and
HAl-1 and treat malignancies that express these proteins on the cell surface as
taught by Foltz et al. with a reasonable expectation of success. This is because Dickson
et al. used the antibody M69 to target cancer cells that expresses both Matriptase and
HAl-1 and thus the specificity of the antibody would have targeted it toward cancer cells and thus avoiding off target effects. Further, a skilled artisan would have found it obvious to conjugate the antibody with Doxorubicin since this was widely known in the art as exemplified by Sivam .The motivation to do so is given by Sivam, which use their
immunoconjugates for specific and targeted treatment of doxorubicin resistant cells,
which would thus intracellularly integrate the doxorubicin and avoid drug resistance.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 4-8 are rejected on the ground of nonstatutory double patenting as being
unpatentable over claim 1-13 of the U.S. Pat. No. 9,682,094. Although the claims at issue are not identical, they are not patentably distinct from each other because it is apparent that the U.S. Patent anticipate the instant claims.
Claims 1-3 are rejected on the ground of nonstatutory double patenting as being
unpatentable over claim 1-3 of the U.S. Pat. No. 9,849,192. Although the claims at issue are not identical, they are not patentably distinct from each other because it is apparent that the U.S. Patent anticipate the instant claims.
Claims 1-8 are rejected on the ground of nonstatutory double patenting as being
unpatentable over claim 1-10 of the U.S. Pat. No. 10,376,597. Although the claims at
issue are not identical, they are not patentably distinct from each other because it is
apparent that the U.S. Patent anticipate the instant claims.
Conclusion
No claims are allowed.
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ELLY-GERALD STOICA
Primary Examiner
Art Unit 1647
/Elly-Gerald Stoica/Primary Examiner, Art Unit 1647
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