DETAILED ACTION
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 .
1. Claims 1-10, 14-17, 29, 31, and 36-42 are currently under consideration.
Specification
2. The use of the term Herceptin, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
3. Claims 8-10 and 14-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 8 recites the limitation "the VH-2 and VL-2" in line 2. There is insufficient antecedent basis for this limitation in the claim because the claims from claim 8 depends do not recite a “VH-2 and VL-2".
Claim 14 recites the limitation "the VH-1 and VL-1" in line 2. There is insufficient antecedent basis for this limitation in the claim because the claims from claim 8 depends do not recite a “VH-1 and VL-1 ".
Dependent claims 9, 10 and 15-17 are also rejected as they incorporate the indefinite limitations by reference to claims 8 or 14.
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.
4. Claim 1-10, 14-17, 29, 31, and 36-42 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 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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (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 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. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the claimed genus
The claims are drawn broadly drawn to a construct comprising a first antigen-binding domain that specifically binds to human HER2, and a second antigen-binding domain that specifically binds to human Trop-2. Claims like claims 3-5 and 29 recite CDR, heavy or light chain sequences that bind HER2 or Trop-2, but encompass binding constructs that are not limited to the disclosed HER2 or Trop-2 antigen binding domain sequences. Additionally, claim 29 recites and encompasses significant variants of the claimed heavy and light chain sequences. Thus the claims encompass a large genus of constructs with a first antigen-binding domain that specifically binds to human HER2, and a second antigen-binding domain that specifically binds to human Trop-2.
State of the Relevant Art
As was well-known in the antibody art, antibodies as a class share an overall structure generally comprising two heavy chain polypeptides that each comprises a heavy chain variable region (VH) and a heavy chain constant region made up of several domain (CH1, hinge, CH2, CH3, and for some antibodies, a CH4). Each of the heavy chains pairs with a light chain polypeptide that comprises a light chain variable region (VL) and a constant region. But while this overall structure is shared amongst antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level. By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. See Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33 (see Section 3) “Antibody Structure and the Antigen Binding Site” and Figure 1). Chimeric antibodies comprise the heavy and light chain variable regions of a rodent antibody linked to human constant regions and preserve the entirety of the VH and VL of the parent antibody. Id. at 1619-20. Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4. Almagro provides a detailed discussion regarding various methods of humanization, including rationale design approaches and empirical approaches based on random screening. Almagro, Sections 4 and 5.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure 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 Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“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.”) Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
Summary of Species disclosed in the original specification
The specification teaches the anti-Trop-2 antibody A1,2X4 of SEQ ID NOs: 4 and 5, anti-HER2 antibody of Herceptin of SEQ ID NOs: 7 and 8, and the anti-Trop-2 RS7 antibody of SEQ ID NOs: 10 and 11 and bispecific antibodies comprising these domains. See Example 8 and SEQUENCE Table on pp. 111-118. The specification teaches the binding domain of the bispecific constructs can have identity of at least about 80% to the disclosed sequences. See p. 56-¶ 0174.
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that 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.
The specification discloses the reduction to practice of five bispecific antibodies (HT2, TH2, HB1, BH1 and BH2) constructed from the Trop-2 antibodies A1,2X4 and RS7 and the HER2 antibody Trastuzumab. The specification does not actually produce any other bispecific antibodies that bind HER2 and TROP2. Antibodies produced by different methods, such as in different species, in phage or with different domains of HER2 or TROP2 , would have been generally expected to be highly structurally diverse, particularly in the CDR sequences. Thus, while applicant has described five species within the recited genus, the genus is very large and there is only one described species for each genus. The described species therefore cannot be considered representative of recited genus of HER2 and Trop-2 binding constructs as claimed. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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. To meet this requirement in the instant case, the specification must describe structural features that convey the claimed binding activity, a prerequisite for utility in the recited methods of treating.
As noted above, the art generally accepted that the combination of the CDRs within the VH and VL pair of an antibody were essential for binding specificity. But the specification does not describe what residues within the CDRs confer the binding activity claimed. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for antibodies other than those comprising either all six CDRs (in the context of VH and VL regions) of one parental antibody, or the VH and VL of one parental antibody.
For all of the reasons presented above, one of skill in the art would not know which of the countless other bispecific antibodies encompassed by the claims that meet the highly general structural requirements of the claims would also be able to specifically bind human HER2 and human Trop-2. Neither the specification nor the dependent claims provide sufficient additional structure or a structure/function correlation to provide an adequate written description of the genus claimed. Therefore, the skilled artisan would not reasonably conclude that the inventors, at the time the application was filed, had full possession of a construct comprising a first antigen-binding domain that specifically binds to human HER2, and a second antigen-binding domain that specifically binds to human Trop-2 as broadly claimed. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
Claim Rejections - 35 USC § 112
5. Claim 42 is 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 a method of treating a cancer expressing HER2 and/or Trop-2 in a subject, comprising administering to said subject the construct of claim 1, does not reasonably provide enablement for a method of treating a disease or condition in a subject, comprising administering to said subject the construct of claim 1. 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.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claim is broadly drawn to a method of treating a disease or condition in a subject, comprising administering to said subject the construct of claim 1. Thus, the claim encompass treating any disease or condition, including any cancer, with the construct of claim 1.
The specification teaches that drug conjugated bispecific antibodies (HT2-BI-P203, HT0002-MMAE, HB1-DM1) had in vitro cytotoxic activity against cancer cell lines high levels of HER2 and/or TROP2, but not the unconjugated HT2 antibody. See Example 5, Tables 2-4 and 9A-C.
The specification teaches that the drug conjugated bispecific antibodies HT002-BI-P203 and A1,2X4-BI-P203 had in vivo anti-tumor activity against HER2 and TROP2 expressing cancers . See Example 6 and Figs. 10 and 11.
The specification teaches that the drug conjugated bispecific antibodies HT0002-MMAE and A1,2X4-MMAE and the unconjugated HT0002 had in vivo anti-tumor activity against HER2 and TROP2 expressing cancer. See Examples 7 and 8 and Figs. 12 and 13.
One of skill in the art cannot extrapolate the teachings of the specification to the enablement of the scope of the claim because the specification has only demonstrated treating HER2 and TROP2 expressing cancers with the HER2 and TROP2 bispecific antibodies, but the claim is drawn to treating any disease or condition with the HER2 and TROP2 bispecific antibodies and the development of novel therapeutics is unpredictable. In particular, it is well known that the art of anti-cancer therapy is highly unpredictable, for example, Gura (Science, 1997, 278:1041-1042) teaches that researchers face the problem of sifting through potential anticancer agents to find ones promising enough to make human clinical trials worthwhile and teach that since formal screening began in 1955, many thousands of drugs have shown activity in either cell or animal models that only 29 have actually been shown to be useful for chemotherapy See p. 1041, see 1st and 2nd para. Furthermore, Kaiser (Science, 2006, 313: 1370) teaches that 90% of tumor drugs fail in patients. See 3rd col., 2nd to last para. Additionally, Chames et al (British J. of Pharmacology, 2009, 157, 220-233) teaches that there are several challenges to development therapeutic antibodies. These challenges include functional limitations such as inadequate pharmacokinetics, tissue accessibility and impaired interactions with the immune system (Abstract). Chames teaches several limitations of therapeutic antibodies such as affinity between the antibody and its antigen, competition with patient’s IgG, and efficiency issues in triggering the immune response (pages 224-225). Further Young et al. (US Patent Application Pub. 2004/0197328, October 7, 2004) teach that even for monoclonal antibodies that recognize the same protein, it cannot be predicted if the antibody will be of therapeutic benefit. In particular, Young et al. teach that while monoclonal antibody 11BD-2E11-2, which recognizes Melanoma-associated chondroitin sulfate proteoglycan (MCSP), is effective for treatment of breast and ovarian tumors (see examples 7 and 8), other monoclonal antibodies that also recognize MCSP, such as 9.2.27 and 225.28S, were ineffective as therapeutic antibodies See ¶¶ 0014-0019. Thus, because of the known unpredictability of the art, in the absence of experimental evidence with data commensurate in scope with the invention claimed, one of skill in the art could not predictably make and use the broadly claimed method of treatment without undue experimentation for the reasons set forth above.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
6. Claim(s) 1-10, 14-17, 29, 31, and 36-42 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/142659 A2 (Bhowmik et al. July 09, 2020), “Bhowmik” in view of US 2003/0228663 A1 (Lowman et al. Dec 11, 2003), “Lowman”.
Bhowmik teaches multispecific antibodies that bind tumor antigens for the treatment of cancers in human subjects. See abstract, ¶¶ 0001-0006, 0240 and 0281, and Fig. 1A-1D.
Bhowmik teaches the multispecific antibodies can bind to human HER2 and TROP2. See ¶¶ 0059-0060, 0065, 0089, 0378-0381, 0240 and 0281, Table 6-p. 117, Example 20 and claim 4.
Bhowmik teaches that the multispecific antibodies can bind more than one antigen, particularly two, three, four or more antigens including at least one tumor antigen. See ¶¶ 0292-0293.
Bhowmik teaches that the multispecific antibodies can comprise the CDRs and VH/VL of the TROP-2 antibody RS7 and the HER 2 antibody Trastuzumab. See ¶¶ 0082, 0089, and 0103 Tables 1 and 2.
Bhowmik teaches the TROP-2 antibody can comprise the HC variable region of SEQ ID NO: 9, which comprises the TROP2 antibody sequences of SEQ ID NOs: 10, 38, 39 and 40 of claims 3 and 5. See ¶¶ 0084 and 0103-0108, Table 1 and Appendix.
Bhowmik teaches the TROP-2 antibody can comprise the LC variable region of SEQ ID NO: 10, which comprises the TROP2 antibody sequences of SEQ ID NOs: 41, 42 and 43 and has 99% identity to SEQ ID NO: 11 of claims 3 and 5. See ¶¶ 0084 and 0103-0108, Table 2 and Appendix.
Bhowmik teaches the antibodies of the multispecific antibody can be full length antibodies, Fab, F9ab’)2, Fv and a single chain Fv (scFv) with an Fc domain. See ¶¶ 0052-0055 and Fig. 1A.
Bhowmik teaches the different antibody domains of the multispecific antibody can be fused together with linkers. See ¶¶ 0053-0055 and Fig. 1A.
Regarding claim 29, SEQ ID NO: 9 of Bhowmik has 100% identity to SEQ ID NO:20 and SEQ ID NO: 10 of Bhowmik has 99% identity to SEQ ID NO:21. See Appendix.
Regarding claim 31, Bhowmik teaches the multispecific antibody can be conjugated to at least two therapeutic or cytotoxic moiety with linkers. See ¶¶ 0002, 0049 and 0160-0181 and Fig. 1B.
Regarding claim 36, given that the multispecific antibodies of Bhowmik bind to human HER2 and TROP2 they would compete with other antibodies binding human HER2 and/or TROP2.
Regarding claim 37, Bhowmik teaches making pharmaceutical compositions with pharmaceutically acceptable carries for the multispecific antibodies. See ¶¶ 0006 and 0251-0269.
Regarding claims 38-41, Bhowmik teaches nucleic acids and nucleic acid vectors for producing the for the multispecific antibodies for production of the antibodies from cultured host cells. . See ¶¶ 0136-0141 and 0143-0159.
Regarding claims 42, Bhowmik teaches treating cancer with the multispecific antibodies of the invention . See ¶¶ 0002, 0006, and 0198-0214, Table 6 and Example 20.
Bhowmik teaches TROP2 and HER2 are expressed in various cancers separately and together including breast, cervical, colon and esophageal cancer. See Table 6.
Bhowmik teaches as set forth above, but does not teach a working example of a multispecific antibody that binds to human HER2 and Trop-2 or the sequences of Trastuzumab.
Lowman teaches the humanized monoclonal antibody hu4D5-8 is Trastuzumab and is used as a therapeutic in the treatment of breast cancer. See ¶¶ 0125 and 0234.
Lowman teaches making bispecific antibodies with the anti-HER2 antibodies. See ¶¶ 0139-0147.
Lowman teaches the hu4D5-8/Trastuzumab light chain of SEQ ID NO: 1 which comprises SEQ ID NO: 8 of claim 5 and SEQ ID NOs: 35-37 of claim 4. See ¶¶ 0234 and Appendix.
Lowman teaches the hu4D5-8/Trastuzumab heavy chain of SEQ ID NO: 2 which comprises SEQ ID NO: 7 of claim 5 and SEQ ID NOs: 32-34 of claim 4. See ¶¶ 0234 and Appendix.
It would have been prima facie obvious at the time the invention was filed given that the level of skill in the art was high to combine the teachings of Bhowmik and Lowman and target human HER2 and human TROP2 with the multispecific antibodies of Bhowmik because Bhowmik teaches that the multispecific antibodies can bind two or more tumor antigens in human subjects, Bhowmik teaches that the multispecific antibodies can bind HER2 and TROP2 with antibodies like Trastuzumab and RS7, respectively, Bhowmik teaches that HER2 and TROP2 are expressed in multiple cancers and Lowman teaches the Trastuzumab is used as a therapeutic in the treatment of breast cancer and can be part of a bispecific antibody. Thus, one would have been motivated to target human HER2 and human TROP2 with the multispecific antibodies of Bhowmik to enhance the targeting of tumors that express one or both antigens.
Conclusion
7. No claims allowed. It is noted that “ wherein: a) the VH-2 comprises a HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26, a HC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27, and a HC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28, and the VL-2 comprises a LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 29, a LC-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 30, and a LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31” of claim 3 and wherein “b1) a HC-CDR1, a HC-CDR2, and a HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the V.sub.H-2 having the sequence set forth in SEQ ID NO: 4, and a LC-CDR1, a LC-CDR2, and a LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within the V.sub.L-2 having the sequence set forth in SEQ ID NO: 5” of claim 5 are free of prior art.
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Greg Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/PETER J REDDIG/Primary Examiner, Art Unit 1646
APPENDIX
SEQ ID NO 10 alignment with SEQ ID NO: 9 of Bhowmik
ID BHZ90876 standard; protein; 121 AA.
XX
AC BHZ90876;
XX
DT 03-SEP-2020 (first entry)
XX
DE Anti-TROP2 antibody VH alpha-TROP2, SEQ ID 9.
XX
KW EGP-1; EGP1; GA733-1; GA7331; GP50; MIS1; TACSTD2; TROP2;
KW antibody therapy; cancer; cell proliferation; cytostatic;
KW gastrointestinal-gen.; heavy chain variable region;
KW hematological neoplasm; hematological-gen.; hepatotropic;
KW immunosuppressive; liver tumor; single chain antibody; t-lymphocyte;
KW therapeutic; tumor-associated calcium signal transducer 2.
XX
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 31..35
FT /label= CDR1
FT Region 50..66
FT /label= CDR2
FT Region 99..110
FT /label= CDR3
XX
CC PN WO2020142659-A2.
XX
CC PD 09-JUL-2020.
XX
CC PF 03-JAN-2020; 2020WO-US012139.
XX
PR 04-JAN-2019; 2019US-0788495P.
XX
CC PA (TRIO-) TRIO PHARM INC.
XX
CC PI Bhowmik S, Brady WA;
XX
DR WPI; 2020-62165N/060.
XX
CC PT New multi-specific antibody comprising tumor binding moiety that
CC PT specifically binds to a tumor-associated antigen and immune cell binding
CC PT moiety binding to antigen expressed on immunosuppressive cell, used to
CC PT treat e.g. cancer.
XX
CC PS Claim 9; SEQ ID NO 9; 209pp; English.
XX
CC The present invention relates to a novel multi-specific antibody, useful
CC for treating a disease or condition in a subject. The multi-specific
CC antibody comprises a tumor binding moiety that specifically binds to a
CC tumor-associated antigen and an immune cell binding moiety that
CC specifically binds to an antigen expressed on an immunosuppressive cell.
CC The invention further relates to: a pharmaceutical composition comprising
CC the multi-specific binding polypeptide; a nucleic acid encoding a multi-
CC specific antibody; a method for treating a disease or condition in a
CC subject; a method for inducing tumor and immunosuppressive cell killing
CC effect in a target cell population; a method for inducing
CC immunosuppressive cell killing in the subject; a method for activating
CC tumor cell-killing immune cells in the subject; a method for reducing
CC suppression of tumor cell-killing immune cells in the subject. The
CC antibody comprises heavy chain variable region (VH) corresponds to SEQ ID
CC NOs: 9, 16, 20, 24 or 28 (see BHZ90876, BHZ90883, BHZ90887, BHZ90891 or
CC BHZ90895) and light chain variable region (VL) corresponds to SEQ ID NOs:
CC 10, 32, 36, 40 or 44 (see BHZ90877, BHZ90899, BHZ90903, BHZ90907 or
CC BHZ90911). The pharmaceutical composition of the invention enhances T-
CC cell proliferation, optionally tumor-infiltrating lymphocyte (TIL)
CC proliferation. The disease or conditions include cancers. The disease or
CC condition includes bladder cancer, bone cancer, brain cancer, breast
CC cancer, cervical cancer, cholangiocarcinoma, colorectal cancer,
CC endometrial cancer, esophageal cancer, eye cancer, head and neck cancer,
CC kidney cancer, liver cancer, lung cancer, melanoma, ovarian cancer,
CC pancreatic cancer, prostate cancer, sarcoma, stomach cancer, testicular
CC cancer, or thyroid cancer, the breast cancer is luminal A breast cancer,
CC luminal B breast cancer, triple-negative breast cancer, HER2-enriched
CC breast cancer, or normal-like breast cancer, the breast cancer is triple-
CC negative breast cancer, hematological malignancy (chronic lymphocytic
CC leukemia (CLL), acute myeloid leukemia (AML), diffuse large B-cell
CC lymphoma (DLBCL), chronic myeloid leukemia, or acute myeloid leukemia),
CC or liver disease or condition (non-alcoholic fatty liver disease (NASH)
CC or alcoholic steatohepatitis).
XX
SQ Sequence 121 AA;
ALIGNMENT:
Query Match 100.0%; Score 654; Length 121;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTY 60
Qy 61 TDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVS 120
Qy 121 S 121
|
Db 121 S 121
ALIGNMENT OF SEQ ID NOs: 38-40 with SEQ ID NO: 9 of Bhowmik:
Query Match 88.0%; Score 180.4; Length 121;
Best Local Similarity 42.5%;
Matches 34; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 NYGMN--------------WINTYTGEPTYTDDFKG------------------------ 22
||||| |||||||||||||||||
Db 31 NYGMNWVKQAPGQGLKWMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADD 90
Qy 23 --------GGFGSSYWYFDV 34
||||||||||||
Db 91 TAVYFCARGGFGSSYWYFDV 110
SEQ ID NO: 11 alignment with SEQ ID NO: 10 of Bhowmik
ID BHZ90877 standard; protein; 107 AA.
XX
AC BHZ90877;
XX
DT 03-SEP-2020 (first entry)
XX
DE Anti-TROP2 antibody VL alpha-TROP2, SEQ ID 10.
XX
KW EGP-1; EGP1; GA733-1; GA7331; GP50; MIS1; TACSTD2; TROP2;
KW antibody therapy; cancer; cell proliferation; cytostatic;
KW gastrointestinal-gen.; hematological neoplasm; hematological-gen.;
KW hepatotropic; immunosuppressive; light chain variable region;
KW liver tumor; single chain antibody; t-lymphocyte; therapeutic;
KW tumor-associated calcium signal transducer 2.
XX
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 24..34
FT /label= CDR1
FT Region 50..56
FT /label= CDR2
FT Region 89..97
FT /label= CDR3
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CC PN WO2020142659-A2.
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CC PD 09-JUL-2020.
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CC PF 03-JAN-2020; 2020WO-US012139.
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PR 04-JAN-2019; 2019US-0788495P.
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CC PA (TRIO-) TRIO PHARM INC.
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CC PI Bhowmik S, Brady WA;
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DR WPI; 2020-62165N/060.
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CC PT New multi-specific antibody comprising tumor binding moiety that
CC PT specifically binds to a tumor-associated antigen and immune cell binding
CC PT moiety binding to antigen expressed on immunosuppressive cell, used to
CC PT treat e.g. cancer.
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CC PS Claim 9; SEQ ID NO 10; 209pp; English.
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CC The present invention relates to a novel multi-specific antibody, useful
CC for treating a disease or condition in a subject. The multi-specific
CC antibody comprises a tumor binding moiety that specifically binds to a
CC tumor-associated antigen and an immune cell binding moiety that
CC specifically binds to an antigen expressed on an immunosuppressive cell.
CC The invention further relates to: a pharmaceutical composition comprising
CC the multi-specific binding polypeptide; a nucleic acid encoding a multi-
CC specific antibody; a method for treating a disease or condition in a
CC subject; a method for inducing tumor and immunosuppressive cell killing
CC effect in a target cell population; a method for inducing
CC immunosuppressive cell killing in the subject; a method for activating
CC tumor cell-killing immune cells in the subject; a method for reducing
CC suppression of tumor cell-killing immune cells in the subject. The
CC antibody comprises heavy chain variable region (VH) corresponds to SEQ ID
CC NOs: 9, 16, 20, 24 or 28 (see BHZ90876, BHZ90883, BHZ90887, BHZ90891 or
CC BHZ90895) and light chain variable region (VL) corresponds to SEQ ID NOs:
CC 10, 32, 36, 40 or 44 (see BHZ90877, BHZ90899, BHZ90903, BHZ90907 or
CC BHZ90911). The pharmaceutical composition of the invention enhances T-
CC cell proliferation, optionally tumor-infiltrating lymphocyte (TIL)
CC proliferation. The disease or conditions include cancers. The disease or
CC condition includes bladder cancer, bone cancer, brain cancer, breast
CC cancer, cervical cancer, cholangiocarcinoma, colorectal cancer,
CC endometrial cancer, esophageal cancer, eye cancer, head and neck cancer,
CC kidney cancer, liver cancer, lung cancer, melanoma, ovarian cancer,
CC pancreatic cancer, prostate cancer, sarcoma, stomach cancer, testicular
CC cancer, or thyroid cancer, the breast cancer is luminal A breast cancer,
CC luminal B breast cancer, triple-negative breast cancer, HER2-enriched
CC breast cancer, or normal-like breast cancer, the breast cancer is triple-
CC negative breast cancer, hematological malignancy (chronic lymphocytic
CC leukemia (CLL), acute myeloid leukemia (AML), diffuse large B-cell
CC lymphoma (DLBCL), chronic myeloid leukemia, or acute myeloid leukemia),
CC or liver disease or condition (non-alcoholic fatty liver disease (NASH)
CC or alcoholic steatohepatitis).
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SQ Sequence 107 AA;
ALIGNMENT:
Query Match 99.3%; Score 549; Length 107;
Best Local Similarity 99.1%;
Matches 106; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPD 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVDIK 107
||||||||||||||||||||||||||||||||||||||||||||:||
Db 61 RFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIK 107
ALIGNMENT OF SEQ ID NOs: 41-43 with SEQ ID NO: 10 of Bhowmik:
Query Match 81.6%; Score 109.3; Length 107;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 KASQDVSIAVA---------------SASYRYT--------------------------- 18
||||||||||| |||||||
Db 24 KASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDF 83
Qy 19 -----QQHYITPLT 27
|||||||||
Db 84 AVYYCQQHYITPLT 97
Alignment of SEQ ID NO: 20 with SEQ ID NO: 9 of Bhowmik
Title: US-18-273-509-20
Perfect score: 3752
Sequence: 1 QVQLQQSGSELKKPGASVKV..........GDGFYAMDYWGQGTLVTVSS 701
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 121 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 1 summaries
Database : US-17-420-000-9.pep:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 654 17.4 121 1 US-17-420-000-9 MULTI-SPECIFIC PRO
ALIGNMENTS
RESULT 1
US-17-420-000-9
Query Match 17.4%; Score 654; DB 1; Length 121;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTY 60
Qy 61 TDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVS 120
Qy 121 S 121
|
Db 121 S 121
Alignment of SEQ ID NO: 21 with SEQ ID NO: 10 of Bhowmik
Title: US-18-273-509-21
Perfect score: 1106
Sequence: 1 DIQLTQSPSSLSASVGDRVS..........VTIIQGLSSPVTKSFNRGEC 215
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 107 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 1 summaries
Database : US-17-420-000-10.pep:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 549 49.6 107 1 US-17-420-000-10 MULTI-SPECIFIC PRO
ALIGNMENTS
RESULT 1
US-17-420-000-10
Query Match 49.6%; Score 549; DB 1; Length 107;
Best Local Similarity 99.1%;
Matches 106; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPD 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVDIK 107
||||||||||||||||||||||||||||||||||||||||||||:||
Db 61 RFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIK 107
SEQ ID NO: 7 alignment with SEQ ID NO: 2 of Lowman
US-10-410-894-2
Filing date in PALM: 2003-04-09
Sequence 2, US/10410894
Publication No. US20030228663A1
GENERAL INFORMATION
APPLICANT: GENENTECH, INC.
APPLICANT: LOWMAN, Henry B.
APPLICANT: GERSTNER, Resi B.
APPLICANT: CARTER, Paul J.
TITLE OF INVENTION: ANTI-HER2 ANTIBODY VARIANTS
FILE REFERENCE: 39766-0108 US
CURRENT APPLICATION NUMBER: US/10/410,894
CURRENT FILING DATE: 2003-04-09
NUMBER OF SEQ ID NOS: 24
SEQ ID NO 2
LENGTH: 120
TYPE: PRT
ORGANISM: homo sapiens
ALIGNMENT:
Query Match 100.0%; Score 645; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRY 60
Qy 61 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 120
SEQ ID NO: 8 alignment with SEQ ID NO: 1 of Lowman
Sequence 1, US/10410894
Publication No. US20030228663A1
GENERAL INFORMATION
APPLICANT: GENENTECH, INC.
APPLICANT: LOWMAN, Henry B.
APPLICANT: GERSTNER, Resi B.
APPLICANT: CARTER, Paul J.
TITLE OF INVENTION: ANTI-HER2 ANTIBODY VARIANTS
FILE REFERENCE: 39766-0108 US
CURRENT APPLICATION NUMBER: US/10/410,894
CURRENT FILING DATE: 2003-04-09
NUMBER OF SEQ ID NOS: 24
SEQ ID NO 1
LENGTH: 109
TYPE: PRT
ORGANISM: homo sapiens
Query Match 100.0%; Score 557; Length 109;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPS 60
Qy 61 RFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK 107