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 .
DETAILED ACTION
The Amendment filed 12/17/2025 in response to Office Action of 9/17/2025, is acknowledged and has been entered. Claims 1-4, 6, 11, 14-16, 20, and 40-46 are now pending. Claim 1 is amended. Claims 40-46 are new. Claims 1-4, 6, 11, 14-16, 20, and 40-46 are currently being examined.
Maintained Rejection
(Amendments and Arguments Addressed)
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 1-4, 6, 11, 14-16, 20, and 40-46 remain 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a composition for treating cancer which is resistant to EGFR inhibition comprising: (a) a means for specifically binding the extracellular part of EGFR and the extracellular part of HER2; and (b) a means for specifically binding the extracellular part of EGFR and the extracellular part of HER3; wherein the means for binding to an extracellular part of EGFR binds domain I or domain III of EGFR; the means for specifically binding to an extracellular part of HER2 binds domain I or domain IV of HER2; and the means for specifically binding to an extracellular part of HER3 binds to domain III of HER3. The claims further recite that the means for binding the extracellular parts of EGFR and HER2 and/or extracellular parts of EGFR and HER3 are variable domains comprised in a bispecific antibody. Thus, the claims identify the “means for binding” as part of a bispecific antibody, where the function of the bispecific antibody is to (1) bind to an extracellular part of EGFR and extracellular part of HER2 and (2) bind to extracellular part of EGFR and extracellular part of HER3. No structure of the “bispecific antibody” or any other “means for binding” is recited.
Dependent claims 14-16 provide partial structure of the variable domains that bind to EGFR, HER2, and HER3, wherein the variants comprise a substitution, deletion, and/or insertion of 1, 2 or 3 amino acids in the CDR’s. Therefore, depending on the SEQ ID NO, this can lead up to 17-60% sequence discrepancies. Thus, the claims identify the variable domains by partial structure, wherein the antigen binding moiety comprise a broad genus of variants having up to 17%-60% sequence discrepancy from any of instantly claimed sequences. The specification fails to disclose any other variants of the variable domains comprising up to 17-60% sequence discrepancy from the instantly claimed sequences.
The instant specification discloses the “means for binding” as binding moieties, and defines these binding moieties as antibodies, multispecific antibodies, or bispecific antibodies. [see at least: 0012, 0035, 0045-0050 of the published instant application] The instant specification discloses 2 EGFR variable domains (MF3755 and MF4280), 2 HER2 variable domains (MF1849 and MF2032), and 1 HER3 variable domain (MF3178). The instant specification fails to disclose any other structure sequences required of the variable domains or binding moieties to possess the functions of binding to extracellular parts of EGFR, HER2, or HER3. The specification also fails to disclose any other variants of the variable domains comprising up to 17-60% sequence discrepancy from the instantly claimed sequences.
With regards to a full-length antibody, it was 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. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7).
In addition, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa H et al. (mAbs 2017, 9(5) 854-873) taught a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis (page 866, last sentence left column). Hasegawa taught the 2 mAbs differed only by one amino acid in the LC's CDR1 and that despite the near-identity of their primary sequences, the parental mAb secreted copious amounts of IgG to the culture media, while the variant mAb induced RB phenotypes extensively and secreted 20-fold less IgG (page 866, right column, first paragraph). Importantly, the 2 model IgGs were by no means abnormal or defective as mAbs, but demonstrated a profound impact of a single amino acid substitution on immunoglobulin biosynthesis. (page 866, right column, first paragraph).
To provide adequate written description and evidence of possession of the claimed “means for binding”, the instant specification can structurally describe representative variable domains of the binding moieties that function to bind extracellular parts of EGFR, HER2, or HER3, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
Although Applicants may argue that it is possible to screen for antigen binding moieties that bind to extracellular parts of EGFR, HER2 or HER3 and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future binding proteins or antibodies yet to be discovered that may function as claimed. The EGFR, HER2, or HER3 antigens provides no information about the structure of the variable domain that binds to it.
In this case, the only factor present in the claims is a recitation of the binding moieties function: “binds an extracellular part of EGFR”, “binds an extracellular part of HER2”, and “binds an extracellular part of HER3”. The claims broadly encompass any binding moiety that functions bind extracellular parts of EGFR, HER2, or HER3. The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses only 3 EGFR binding moieties, 3 HER2 binding moieties, and 2 HER3 binding moieties. A definition by function does not suffice to define the genus because it is only an indication of what the binding moiety does, rather than what it is.
With regards to variants having up to 17-60% sequence discrepancy, depending on the sequence, from the instantly claimed sequences. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the variable domains or CDRs that can be altered and still maintain EGFR, HER2, or HER3 binding function. The instant claims attempt to claim every binding moiety that would achieve a desired result, wherein the instant specification does not describe sufficient representative examples to support the full scope of the claims. Given the well-known high level of polymorphism of binding moieties and antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of binding moieties or variants of the instantly claimed sequences encompassed by the claimed compositions. Therefore, one could not readily envision members of the broadly claimed genus.
Given the lack of representative examples to support the full scope of the claimed binding moieties that bind to EGFR/HER2 or EGFR/HER3, and lack of reasonable structure-function correlation with regards to the unknown sequences in the binding moieties or variable domains or CDRs that provide EGFR, HER2, or HER3 binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of the claimed composition comprising two or more binding moieties that bind to extracellular parts of EGFR/HER2 or EGFR/HER3 that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Examiner’s Suggestion: Amend the claims to recite and require the structure critical to the function of the claimed composition, that is the six CDR SEQ ID Nos from the variable domains of each of the binding moieties. (Amend claim 1 to recite the limitations of claims 40-46)
Response to Arguments
Applicant reiterates the arguments that the specification clearly links the structures to the functions under 35 U.S.C. 112(f) and that the claims are adequately described in the specification.
Applicant’s arguments have been considered but are not persuasive. As stated in the previous argument, although the claims have been amended to recite “means plus function”, the structure disclosed in the written description of the specification must clearly link or associate that structure to the function under 35 U.S.C. 112(f). see MPEP 2181. The text recites that the means for binding is a bispecific antibody, and provides the specific examples in the specification as noted in the text provided by the Applicant. However, the specification also recites that the sequences of the bispecific antibodies can also be a variant thereof. No structure of the full length bispecific antibody is recited.
2181 Identifying and Interpreting a 35 U.S.C. 112(f) or Pre-AIA 35 U.S.C. 112, Sixth Paragraph Limitation [R-07.2022]
C. The Supporting Disclosure Clearly Links or Associates the Disclosed Structure, Material, or Acts to the Claimed Function
The structure disclosed in the written description of the specification is the corresponding structure only if the written description of the specification or the prosecution history clearly links or associates that structure to the function recited in a means- (or step-) plus-function claim limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. See B. Braun Medical Inc., v. Abbott Laboratories, 124 F.3d 1419, 1424, 43 USPQ2d 1896, 1900 (Fed. Cir. 1997). The requirement that a particular structure be clearly linked with the claimed function in order to qualify as corresponding structure is the quid pro quo for the convenience of employing 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, and is also supported by the requirement of 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph, that an invention must be particularly pointed out and distinctly claimed. See Medical Instrumentation & Diagnostics Corp. v. Elekta AB, 344 F.3d 1205, 1211, 68 USPQ2d 1263, 1268 (Fed. Cir. 2003). For a means- (or step-) plus- function claim limitation that invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph, is appropriate if one of ordinary skill in the art cannot identify what structure, material, or acts disclosed in the written description of the specification perform the claimed function.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Maintained Rejection.
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.
Claims 1-4, 6, 11, 15-16, 20 and 40-46 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 limitation "a means for binding" invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. There is no clear indication or association between the structure and the function that can be found in the instant specification. The instant specification discloses that the binding moiety may be: (a) a protein or an aptamer, an antibody, or a variable domain, but there is no specific structure. [see at least paragraphs 0010, 0044 of the published application] There is insufficient disclosure of the structure performing the claimed function. Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
Maintained Rejections
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.
Claim(s) 1-4, 6, 11, 14-16, 20, 40, remain rejected under 35 U.S.C. 103 as being unpatentable over Lantto et al (US9527913 B2 – Published 12/27/2016), in view of Castoldi et al (US20150166670 A1, Published 6/18/2015), Throsby et al (WO2017069628 A2, Published 4/27/2017; of record) and Geuijen et al (WO2015130173 A1, Published: 9/3/2015; of record).
Lantto teaches a composition for treating cancer, which is resistant to EGFR inhibition, comprising two or more binding moieties: wherein each of said binding moieties, such as a bispecific antibody or an IgG, comprises a variable domain that binds to an extracellular part of EGFR; and wherein a first of said binding moieties comprises a variable binding domain that binds to an extracellular part of HER2 and a second of said binding moieties comprises a variable domain that binds to an extracellular part of HER3. [Abstract; col 14 lines 14-66; col 39 lines 30-61; col 41, lines 1-10, col 43, lines 41-62] Lantto also teaches a pharmaceutical composition comprising this composition. [col 45, lines 14-20] Lantto teaches that simultaneous targeting of two or more members of the EGFR-family, such as EGFR, HER2, and HER2) with humanized antibodies leads to effective inhibition of cancer growth. Lantto teaches that antibody mixtures targeting these targets effectively suppress tumor growth in multiple xenograft models of human cancers, and that antibody mixtures retain their inhibitory effect in cells that have acquired resistance to therapeutic monoclonal antibodies that target one EGFR-family member only, such as cetuximab or pertuzumab. [col. 5, lines 40-45; col 14 lines 1-11] Lantto teaches that a mixture comprising at least two humanized antibodies against at least two different receptors, selected from EGFR, HER2, and HER3, and that the individual antibodies may bind to EGFR/HER2 or EGFR/HER3. [cols 39-42] Lantto demonstrates in Examples 3, 4, 7, 8, and 10 that simultaneous targeting of three receptors provided broader efficacy and synergy than targeting of a single receptor or any combination of two receptors in the HER family, and also teaches these in EGFR resistant cancer cell lines. Lantto teaches that ErbB receptors have the ability to replace one another in order to maintain growth stimulatory signaling and a malignant phenotype. Lantto teaches that EGFR contains three domains, including an extracellular domain, including subdomains I-III. and that EGF binds EGFR. Lantto teaches that HER2 consists of an extracellular domain with four subdomains I-IV. Lantto teaches that domains II and IV form two distinct interfaces that stabilize the heterodimer formation of HER2. Lantto teaches that HER3 consists of four extracellular subdomains (I-IV), and teaches that NRG binds to HER3. [col 3-6]
However, Lantto does not explicitly teach: (1) that the CH3-regions of heavy chains of the first and/or second antibody are engineered to facilitate heterodimerization of a heavy chain with an EGFR binding domain with a heavy chain with an HER2 binding variable domain and/or EGFR binding variable domain with a heavy chain with an HER3 binding variable domain, (2) the sequences of the variable domains that bind to extracellular parts of EGFR and HER3, and (3) the specific domains that the variable domains bind to.
Castoldi teaches a composition comprising two or more binding moieties, wherein the binding moieties are antibodies, or bispecific antibodies. Castoldi teaches that the antibody binds to two different antigens, EGFR (“HER1”) /HER2, EGFR (“HER1”)/HER3. [01990202] Castoldi teaches that to improve ratio of desired antibody product compared to undesired side products the CH3 domains can be modified by “knob into holes” technology. Castoldi teaches that in this method, the two CH3 domains are altered to increase heterodimerization of both heavy chains containing these two CH3 domains, which further stabilizes the heterodimers. [0163-0164]
Throsby teaches the known sequences of variable domains that bind to extracellular parts of EGFR and HER3. Throsby teaches the variable domain that binds to an extracellular part of EGFR comprises the heavy chain variable region of SEQ ID NO: 20, which matches 100% to the instantly claimed sequences. See sequence alignments below. Thorsby teaches that these variable domains may be used in bispecific antibodies. [pgs 8-9] Thorsby also teaches methods to increase the percentage of desired bispecific antibodies by engineering CH3 domains to facilitate heterodimerization. [pg 19] Thorsby teaches that variable domain that binds to HER3 blocks the binding of EGFR3 to NRG1. Throsby teaches that the antigen binding site that binds HER3 binds to domain III of HERB3, and that the antigen binding site that binds to EGFR binds to domain III of EGFR.
Variable Domain that binds to extracellular part of EGFR:
SEQ ID NOS: 26-28-30
RESULT 2
BDW03304
(NOTE: this sequence has 12 duplicates in the database searched.
See complete list at the end of this report)
ID BDW03304 standard; protein; 120 AA.
XX
AC BDW03304;
XX
DT 15-JUN-2017 (first entry)
XX
DE Anti-LGR5 antibody MF3755 VH protein SEQ ID NO: 20.
XX
KW G protein coupled receptor 49 protein; LGR5 protein; adenocarcinoma;
KW antibody; antibody therapy; bispecific antibody; breast tumor; cancer;
KW carcinoid tumor; cell proliferation; colorectal tumor; cytostatic;
KW endometrioid carcinoma; expression; head and neck tumor;
KW heavy chain variable region; liver tumor; lung tumor; melanoma;
KW ovary tumor; pancreas tumor; prostate tumor; protein therapy;
KW renal tumor; stomach tumor; testis tumor; therapeutic;
KW uterine cervix tumor.
XX
OS Unidentified.
XX
CC PN WO2017069628-A2.
XX
CC PD 27-APR-2017.
XX
CC PF 21-OCT-2016; 2016WO-NL050726.
XX
PR 23-OCT-2015; 2015EP-00191343.
PR 06-MAY-2016; 2016EP-00168647.
XX
CC PA (NEVW-) KONINK NEDERLANDSE AKAD VAN WETENSCHAPPE.
CC PA (MERU-) MERUS NV.
CC PA (OCEL-) OCELLO BV.
CC PA (REIN-) INST RES BIOMEDICINE IRB BARCELONA.
CC PA (ICRE-) ICREA INST CATALANA RECERCA & ESTUDIS AV.
XX
CC PI Batlle E, Clevers JC, Herpers B, Logtenberg T, Throsby M;
CC PI Vries RGJ;
XX
DR WPI; 2017-27264H/33.
DR N-PSDB; BDW03303.
XX
CC PT New protein that binds extracellular part of membrane associated member
CC PT of epidermal growth factor receptor family or cMET, and extracellular
CC PT part of membrane associated member of WNT signaling pathway used to treat
CC PT cancer e.g. melanoma.
XX
CC PS Disclosure; SEQ ID NO 20; 221pp; English.
XX
CC The invention relates to a novel protein, useful for treating cancer. The
CC invention claims: 1) a bispecific antibody or its functional part,
CC derivative and analogue; 2) a cell system; 3) a method for inhibiting
CC proliferation of a cell that expresses a membrane associated member of
CC EGF receptor family and that expresses a membrane associated member of
CC the WNT pathway in a system permissive for proliferation of the cell; 4)
CC an antibody comprising a variable domain that can bind an epitope on an
CC extracellular part of Leucine-rich repeat-containing G-protein coupled
CC receptor (LGR)-5; and 5) an antibody comprising a variable domain that
CC can bind an epitope on an extracellular part of human EGFR. The protein
CC or antibody or the bispecific antibody is used for treating an individual
CC having cancer such as adenocarcinoma, colorectal cancer, pancreatic
CC cancer, lung cancer, breast cancer, liver cancer, prostate cancer,
CC ovarian cancer, cervical cancer, endometrial cancer, head and neck
CC cancer, melanoma, testis cancer, urothelial cancer, renal cancer, stomach
CC cancer, or carcinoid cancer. The protein or antibody or the bispecific
CC antibody exhibits good antibody-dependent cell-mediated cytotoxicity
CC properties. The present sequence represents an anti-LGR5 antibody heavy
CC chain variable region protein used in the method for inhibiting
CC proliferation of a cell.
XX
SQ Sequence 120 AA;
Query Match 87.3%; Score 169.4; Length 120;
Best Local Similarity 41.8%;
Matches 33; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 NYAMN--------------WINANTGDPTYAQGFTG------------------------ 22
||||| |||||||||||||||||
Db 31 NYAMNWVRQAPGHGLEWMGWINANTGDPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAED 90
Qy 23 --------ERFLEWLHFDY 33
|||||||||||
Db 91 SAVYYCTRERFLEWLHFDY 109
SEQ ID NO: 3
RESULT 1
BDW03304
(NOTE: this sequence has 20 duplicates in the database searched)
ID BDW03304 standard; protein; 120 AA.
XX
AC BDW03304;
XX
DT 15-JUN-2017 (first entry)
XX
DE Anti-LGR5 antibody MF3755 VH protein SEQ ID NO: 20.
XX
KW G protein coupled receptor 49 protein; LGR5 protein; adenocarcinoma;
KW antibody; antibody therapy; bispecific antibody; breast tumor; cancer;
KW carcinoid tumor; cell proliferation; colorectal tumor; cytostatic;
KW endometrioid carcinoma; expression; head and neck tumor;
KW heavy chain variable region; liver tumor; lung tumor; melanoma;
KW ovary tumor; pancreas tumor; prostate tumor; protein therapy;
KW renal tumor; stomach tumor; testis tumor; therapeutic;
KW uterine cervix tumor.
XX
OS Unidentified.
XX
CC PN WO2017069628-A2.
XX
CC PD 27-APR-2017.
XX
CC PF 21-OCT-2016; 2016WO-NL050726.
XX
PR 23-OCT-2015; 2015EP-00191343.
PR 06-MAY-2016; 2016EP-00168647.
XX
CC PA (NEVW-) KONINK NEDERLANDSE AKAD VAN WETENSCHAPPE.
CC PA (MERU-) MERUS NV.
CC PA (OCEL-) OCELLO BV.
CC PA (REIN-) INST RES BIOMEDICINE IRB BARCELONA.
CC PA (ICRE-) ICREA INST CATALANA RECERCA & ESTUDIS AV.
XX
CC PI Batlle E, Clevers JC, Herpers B, Logtenberg T, Throsby M;
CC PI Vries RGJ;
XX
DR WPI; 2017-27264H/33.
DR N-PSDB; BDW03303.
XX
SQ Sequence 120 AA;
Query Match 100.0%; Score 647; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGSELKKPGASVKISCKASGYDFTNYAMNWVRQAPGHGLEWMGWINANTGDPTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGSELKKPGASVKISCKASGYDFTNYAMNWVRQAPGHGLEWMGWINANTGDPTY 60
Qy 61 AQGFTGRFVFSLDTSVSTAYLQISSLKAEDSAVYYCTRERFLEWLHFDYWGQGTLVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AQGFTGRFVFSLDTSVSTAYLQISSLKAEDSAVYYCTRERFLEWLHFDYWGQGTLVTVSS 120
Variable Domain that binds to extracellular part of HER3:
SEQ ID NOS: 33-35-37
BDW03306
ID BDW03306 standard; protein; 124 AA.
XX
AC BDW03306;
XX
DT 15-JUN-2017 (first entry)
XX
DE Anti-LGR5 antibody MF3178 VH protein SEQ ID NO: 22.
XX
KW G protein coupled receptor 49 protein; LGR5 protein; adenocarcinoma;
KW antibody; antibody therapy; bispecific antibody; breast tumor; cancer;
KW carcinoid tumor; cell proliferation; colorectal tumor; cytostatic;
KW endometrioid carcinoma; expression; head and neck tumor;
KW heavy chain variable region; liver tumor; lung tumor; melanoma;
KW ovary tumor; pancreas tumor; prostate tumor; protein therapy;
KW renal tumor; stomach tumor; testis tumor; therapeutic;
KW uterine cervix tumor.
XX
OS Unidentified.
XX
CC PN WO2017069628-A2.
XX
CC PD 27-APR-2017.
XX
CC PF 21-OCT-2016; 2016WO-NL050726.
XX
PR 23-OCT-2015; 2015EP-00191343.
PR 06-MAY-2016; 2016EP-00168647.
XX
CC PA (NEVW-) KONINK NEDERLANDSE AKAD VAN WETENSCHAPPE.
CC PA (MERU-) MERUS NV.
CC PA (OCEL-) OCELLO BV.
CC PA (REIN-) INST RES BIOMEDICINE IRB BARCELONA.
CC PA (ICRE-) ICREA INST CATALANA RECERCA & ESTUDIS AV.
XX
CC PI Batlle E, Clevers JC, Herpers B, Logtenberg T, Throsby M;
CC PI Vries RGJ;
XX
DR WPI; 2017-27264H/33.
DR N-PSDB; BDW03305.
XX
CC PT New protein that binds extracellular part of membrane associated member
CC PT of epidermal growth factor receptor family or cMET, and extracellular
CC PT part of membrane associated member of WNT signaling pathway used to treat
CC PT cancer e.g. melanoma.
XX
CC PS Disclosure; SEQ ID NO 22; 221pp; English.
XX
CC The invention relates to a novel protein, useful for treating cancer. The
CC invention claims: 1) a bispecific antibody or its functional part,
CC derivative and analogue; 2) a cell system; 3) a method for inhibiting
CC proliferation of a cell that expresses a membrane associated member of
CC EGF receptor family and that expresses a membrane associated member of
CC the WNT pathway in a system permissive for proliferation of the cell; 4)
CC an antibody comprising a variable domain that can bind an epitope on an
CC extracellular part of Leucine-rich repeat-containing G-protein coupled
CC receptor (LGR)-5; and 5) an antibody comprising a variable domain that
CC can bind an epitope on an extracellular part of human EGFR. The protein
CC or antibody or the bispecific antibody is used for treating an individual
CC having cancer such as adenocarcinoma, colorectal cancer, pancreatic
CC cancer, lung cancer, breast cancer, liver cancer, prostate cancer,
CC ovarian cancer, cervical cancer, endometrial cancer, head and neck
CC cancer, melanoma, testis cancer, urothelial cancer, renal cancer, stomach
CC cancer, or carcinoid cancer. The protein or antibody or the bispecific
CC antibody exhibits good antibody-dependent cell-mediated cytotoxicity
CC properties. The present sequence represents an anti-LGR5 antibody heavy
CC chain variable region protein used in the method for inhibiting
CC proliferation of a cell.
XX
SQ Sequence 124 AA;
%
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
1 208.4 89.4 124 BCD86321 -- 16 Anti-erbB-3 antibody (MF3178) heavy chain variable region, SEQ 89.
ALIGNMENT:
Query Match 89.4%; Score 208.4; Length 124;
Best Local Similarity 44.6%;
Matches 37; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 GYYMHW--------------INPNSGGTNYAQKFQG------------------------ 22
|||||| ||||||||||||||||
Db 31 GYYMHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDD 90
Qy 23 --------DHGSRHFWSYWGFDY 37
|||||||||||||||
Db 91 TAVYYCARDHGSRHFWSYWGFDY 113
Geuijen teaches human epidermal growth factor receptor family includes EGFR, HER2, and HER3. Geuijen teaches antibodies that bind to these targets, wherein the binding site that binds to HER2 binds to domain I of HER2, and the binding site that binds to HER2 binds to domain III of HER3. Geuijen teaches that the variable domain that binds to an extracellular part of HER3 binds to at least R426 of domain III of HER3. [pg 7] Geuijen teaches that the affinity (KD) of the variable domain that binds to an extracellular part of HER3, for binding to an HER3 positive SK-BR-3 cell is lower than or equal to 2.0 nM. [pg 18, 2nd paragraph]. Geuijen teaches the variable domain that binds to an extracellular HER3 comprises the instantly claimed sequences comprising a substitution of 1 amino acid in the CDR (see sequence alignments below).
Variable Domain that binds to extracellular part of HER3:
SEQ ID NOS: 33-35-37
RESULT 4
BCF44891
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
ID BCF44891 standard; protein; 121 AA.
XX
AC BCF44891;
XX
DT 25-FEB-2016 (revised)
DT 17-DEC-2015 (first entry)
XX
DE Anti-erbB-3 antibody VH region variant (MF6073), SEQ ID 173.
XX
KW ERBB3 protein; Erbb3 tyrosine kinase receptor; HER3 protein; antibody;
KW antibody therapy; bladder cancer; brain tumor; breast tumor; cancer;
KW colon tumor; colorectal tumor; cytostatic; endometrioid carcinoma;
KW esophagus tumor; head and neck tumor; heavy chain variable region;
KW imaging; liver tumor; lung tumor; melanoma; metastasis; mutein;
KW non-small-cell lung cancer; ovary tumor; pancreas tumor; phosphorylation;
KW prophylactic to disease; prostate tumor; renal tumor;
KW salivary gland disease; skin cancer; stomach tumor; therapeutic.
XX
OS Synthetic.
OS Unidentified.
XX
FH Key Location/Qualifiers
FT Region 31..35
FT /note= "CDR1"
FT Region 50..66
FT /note= "CDR2"
FT Region 99..113
FT /note= "CDR3"
XX
CC PN WO2015130173-A1.
XX
CC PD 03-SEP-2015.
XX
CC PF 27-FEB-2015; 2015WO-NL050125.
XX
PR 28-FEB-2014; 2014EP-00157360.
PR 05-MAY-2014; 2014EP-00167066.
XX
CC PA (MERU-) MERUS BV.
XX
CC PI Geuijen CAW, De Kruif CA, Throsby M, Logtenberg T, Bakker ABH;
XX
DR WPI; 2015-51549K/62.
DR N-PSDB; BCF44890.
XX
CC PT New bispecific antibody comprises first antigen-binding site that binds
CC PT receptor tyrosine kinase (ErbB)-2 and second antigen-binding site that
CC PT binds ErbB-3, used for treating subject having ErbB-2, ErbB-3 or ErbB-
CC PT 2/ErbB-3 positive tumor.
XX
CC PS Claim 26; SEQ ID NO 173; 239pp; English.
XX
CC The present invention relates to a novel bispecific antibody for treating
CC a subject having a tumor, preferably receptor tyrosine kinase (ErbB)-2,
CC ErbB-3 or ErbB-2/ErbB-3 positive tumor. The bispecific antibody comprises
CC first antigen-binding site that binds ErbB-2 and second antigen-binding
CC site that binds ErbB-3. The invention further discloses: (1) a method for
CC treating the subject having ErbB-2, ErbB-3 or ErbB-2/ErbB-3 positive
CC tumor or at risk of having the tumor; (2) a method for counteracting the
CC formation of metastasis in a subject having ErbB-2, ErbB-3 or ErbB-2/ErbB
CC -3 positive tumor; and (3) a pharmaceutical composition comprising the
CC bispecific antibody. The bispecific antibody and pharmaceutical
CC composition are useful for treating a subject having or is at a risk of
CC having a tumor including breast cancer, gastric cancer, colorectal
CC cancer, colon cancer, gastro-esophageal cancer, esophageal cancer,
CC endometrial cancer, ovarian cancer, liver cancer, lung cancer including
CC non-small cell lung cancer, clear cell sarcoma, salivary gland cancer,
CC head and neck cancer, brain cancer, bladder cancer, pancreatic cancer,
CC prostate cancer, kidney cancer, skin cancer, or melanoma cell; for
CC counteracting or inhibiting, phosphorylation of Akt, extracellular signal
CC -regulated kinase (ERK) and/or S6 ribosomal protein; and for
CC counteracting the formation of metastasis in the subject having ErbB-2,
CC ErbB-3 or ErbB-2/ErbB-3 positive tumor. The bispecific antibody is also
CC used for imaging. The invention uses bispecific antibodies with an
CC enhanced internalization property, to the same extent as trastuzumab,
CC which results in the reduced ADCC activity. The present sequence is an
CC anti-erbB-3 antibody VH region variant, where the antibody is used in the
CC method for treating a tumor in the subject. Note: The present sequence is
CC designated as MF6073 in Figure 37 which is referred to in Claim 26.
CC
CC Revised record issued on 19-FEB-2016 : Correction to PS line.
XX
SQ Sequence 121 AA;
\
Query Match 87.3%; Score 203.4; Length 121;
Best Local Similarity 43.4%;
Matches 36; Conservative 1; Mismatches 0; Indels 46; Gaps 2;
Qy 1 GYYMHW--------------INPNSGGTNYAQKFQG------------------------ 22
|||||| |||:||||||||||||
Db 31 GYYMHWVRQAPGQGLEWMGWINPSSGGTNYAQKFQGRVTMTRDTSTSTAYMELSRLRSDD 90
Qy 23 --------DHGSRHFWSYWGFDY 37
|||||||||||||||
Db 91 TAVYYCARDHGSRHFWSYWGFDY 113
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to engineer the CH3-regions of the heavy chains of a first and/or second antibody to facilitate heterodimerizations of the heavy chains. One would have been motivated to, and have a reasonable expectation of success, because: (1) Lantto teaches and demonstrates a composition comprising the instantly claimed binding moieties, (2) Castoldi teaches an antibody that binds to two different antigens, such as EGFR/HER2 and EGFR/HER3, and teaches that to improve antibody desired product, CH3 domains are modified via “knobs into holes” technology to stabilize the heterodimers, and (3) Thorsby also teaches methods to increase the percentage of desired bispecific antibodies by engineering CH3 domains to facilitate heterodimerization. Given the recognized need to produce compositions with binding moieties targeting extracellular parts of EGFR/HER2 and EGFR/HER3, and given the known need and methods to produce stable antibody products by engineering CH3 domains, one of skill in the art could have pursued engineering the CH3-regions of the composition of Lantto to facilitate heterodimerizations of the heavy chains of the binding moieties, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to produce the composition of Lantto with the instantly claimed sequences of the variable domains of EGFR and HER3. One would have been motivated to, because: (1) Lantto teaches and demonstrates a composition comprising binding moieties, such as bispecific antibodies, wherein the first binding moiety comprises a variable domain that binds to extracellular parts of EGFR/HER2, and the second binding moiety comprises a variable domain that binds to extracellular parts of EGFR/HER3, (2) Throsby teaches the known sequences of variable domains that bind to extracellular parts of EGFR and HER3, and (3) Thorsby teaches that these variable domains may be used in bispecific antibodies. One would have a reasonable expectation of success, because Lantto teaches and demonstrates compositions targeting of two or more members of the EGFR-family, such as EGFR, HER2, and HER3) with antibodies. Given the known sequences of the variable domains of EGFR and HER3, and given the known methods of combining the targets into binding moieties, such as bispecific antibodies, one of skill in the art could have used the known sequences in the composition of Lantto, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to target the specific domains such as domain I or domain III of EGFR, domain I or domain IV of HER2, and domain III of HER3 with the composition of Lantto. One would have been motivated to, because: (1) Lantto teaches and demonstrates a composition comprising binding moieties, such as bispecific antibodies, wherein the first binding moiety comprises a variable domain that binds to extracellular parts of EGFR/HER2, and the second binding moiety comprises a variable domain that binds to extracellular parts of EGFR/HER3, (2) Lantto teaches the known extracellular domains of each of the targets, (3) Throsby teaches known binding moieties that comprise variable domains that bind to EGFR and HER3, and teaches that these they bind to domain III of EGFR and HER3, respectively, (4) Geuijen teaches use of antibodies that target extracellular parts of HER2 and HER3, wherein the variable domains bind to domain I of HER2 and domain III of HER3, respectively, and (5) Lantto teaches and demonstrates compositions targeting of two or more members of the EGFR-family, such as EGFR, HER2, and HER3) with antibodies. Given the known domains of EGFR, HER2, and HER3, and given the known methods targeting these domains utilizing binding moieties, such as antibodies or bispecific antibodies, one of skill in the art could have produced variable domains that targeted extracellular parts of EGFR/HER2/HER3 subdomains, with a reasonable expectation of success.
Response to Arguments
Applicant argues that the combination of the cited references do not teach or suggest the claimed invention. Applicant reiterates previous arguments and argues that Examiner misapplies the disclosure of Lanto and continues to use improper hindsight.
Applicant’s arguments have been considered but are not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In this instant case, it is the combination of all the prior art that render the claims obvious. Examiner reiterates the teachings of the cited art: (1) Lantto specifically teaches that the “polyclonal antibody” binds to at least two different antigens, and specifically states “the individual antibodies of the antibody composition may thus bind to EGFR and HER2, EGFR and HER3…” [col 39, lines 51-62] Lantto further teaches that simultaneous targeting of two or more members of the EGFR-family, such as EGFR, HER2, and HER2) with humanized antibodies leads to effective inhibition of cancer growth. Lantto teaches that antibody mixtures targeting these targets effectively suppress tumor growth in multiple xenograft models of human cancers, and that antibody mixtures retain their inhibitory effect in cells that have acquired resistance to therapeutic monoclonal antibodies that target one EGFR-family member only, such as cetuximab or pertuzumab. [col. 5, lines 40-45; col 14 lines 1-11] Lantto also demonstrates in Examples 3, 4, 7, 8, and 10 that simultaneous targeting of three receptors provided broader efficacy and synergy than targeting of a single receptor or any combination of two receptors in the HER family, and also teaches these in EGFR resistant cancer cell lines. Thus, contrary to the Applicant’s arguments, Lantto specifically teaches targeting all three antigens with multiple bispecific antibodies. See images below taken directly from Lantto:
PNG
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543
474
media_image1.png
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Column 39
PNG
media_image2.png
483
474
media_image2.png
Greyscale
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Thus, Lantto provides motivation and reasonable expectation of success for the composition.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 PM.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600