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 .
Claim Status
Applicant’s amendments and remarks, filed 12/11/2025, are acknowledged.
Claims 1-29, 35-39, 43, and 45-47 are canceled.
Claims 30, 42, 44, and 48 are amended.
Claims 49-53 are new.
Claims 30-34, 40-42, 44, and 48-53 are pending.
Claims 48 and 51 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/17/2025.
As such, claims 30-34, 40-42, 44, 49, 50, and 52-53 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Withdrawn Objections
The amino acid sequence disclosure objections are withdrawn. Issues regarding the specification and the drawings missing sequence identifiers have been sufficiently addressed through amendments to the claims filed on 12/11/2025.
The specification objections are withdrawn in part. Issues regarding minor informalities have been sufficiently addressed through amendments to the specification on 12/11/2025.
The claim objections are withdrawn. Issues regarding minor informalities have been sufficiently addressed through amendments to the claims filed on 12/11/2025.
Withdrawn Rejections
Applicant’s arguments, see page 11, filed 12/11/2025, with respect to claims 35, 36, 39, and 42 rejected under 35 USC 112(b) as allegedly being indefinite have been fully considered and are persuasive. The issue regarding the claims comprising indefinite language have been sufficiently addressed through amendments to the claims. Further, Examiner acknowledges that claims 35, 36, and 39 are canceled thus rendering the rejection moot. As such, the rejection under 35 USC 112(b) is withdrawn.
The rejections of claims 30-44 under 35 USC 112(a) as allegedly failing to comply with the written description and enablement requirements are modified in favor of the new limitations added in the amendment filed 12/11/2025. Specifically, Examiner acknowledges that base claims 30 and 44 were amended to recite sequences of the first and second antigen-binding site heavy chain variable regions and a common light chain. Applicant’s arguments, see pages 11-13, filed 12/11/2025, with respect to claims 30-44 rejected under 35 USC 112(a) have been fully considered.
The rejections of claims 30-34, 40-42, and 44, and claims 30-44 under 35 USC 103 as being unpatentable over Roovers et al and further in view of Prewett et al, and Throsby et al and further in view of Prewett et al, respectively, are modified in favor of the new limitations added in the amendment filed 12/11/2025. Specifically, Examiner acknowledges that base claims 30 and 44 were amended to recite sequences of the first and second antigen-binding site heavy chain variable regions and a common light chain. Applicant’s arguments, see pages 13-16, filed 12/11/2025, with respect to claims 30-34, 40-42, and 44, and claims 30-44 rejected under 35 USC 103 have been fully considered.
New Objections and Rejections Necessitated by Amendment
Drawings
The drawings are objected to because Figure 9f recites “CDR3 – QQSYSTPPT (SEQ ID NO: 120); however, the specification recites “an LCDR3 comprising the amino acid sequence QQSYSTP” (see page 23, lines 43 and 44; page 24, lines 5 and 6).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112(b)
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 30-34, 40-42, 44, 49-50, and 52-53 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.
Claims 30 and 44 require complementarity determining regions (CDRs) from heavy and light chain sequences without actually setting forth the CDR sequences. There are several well-established methods to determine CDRs. Using common methods to identify the CDRs produces variable CDR sequences. For example, numbering by the Chothia method produces CDRs that differ in residues than numbering by the Kabat method. Therefore, the methods do not name the same CDRs, and one of skill in the art would not know which of these embodiments would meet the requirements of the claims. The differences in CDRs may have different affinities that would not be capable of the required functions. As such, claims 30, 40, and their dependent claims are rejected.
Claims 30 and 44 have been amended to introduce terms or phrases that are referenced parenthetically. It is unclear, due to the presence of the parentheses, if the terms/phrases are intended as limitations of the claims, or are merely exemplary. In particular, the antibody clone names provided are arbitrary terms that as indicated in the instant specification, could have up to 15 amino acid variations in each chain. The clone name therefore does not identify a specific sequence, and it is unclear if the sequences listed in the parentheses are required limitations for the invention.
Maintained Objections and Rejections
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see pages 10 and 12). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term ATCC, Perkin Elmer, R&D Systems, Ensembl, BIAcore, Becton Dickinson, Nanobodies®, GenBank, Invitrogen, FreeStyle, Gibco, Pierce, Millipore, Octet, Forte-Bio, Sigma Aldrich, Ultracel, GlutaMax, Peprotech, and Tocris, 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.
Applicant’s Arguments
Applicant respectfully requests that the objection be reconsidered and withdrawn. Applicant asserts that a substitute specification addressing each of the objections is provided. (see page 10 of the Remarks filed 12/11/2025)
Response to Arguments
Applicant's arguments filed 12/11/2025 have been fully considered but they are not persuasive in part. Examiner acknowledges the amendments to the specification. However, the amendments do not overcome the objection because the hyperlinks remain browser-executable by listing the “www” at the beginning of the link. As stated in MPEP 608.01(VII): When a patent application with embedded hyperlinks and/or other forms of browser-executable code issues as a patent (or is published as a patent application publication) and the patent document is placed on the USPTO webpage, when the patent document is retrieved and viewed via a web browser, the URL is interpreted as a valid HTML code and it becomes a live web link. When a user clicks on the link with a mouse, the user will be transferred to another webpage identified by the URL, if it exists, which could be a commercial website. USPTO policy does not permit the USPTO to link to any commercial sites since the USPTO exercises no control over the organization, views or accuracy of the information contained on these outside sites.
Further, the amended specification has not addressed the unmarked trademark/names recited in the specification (see for example page 15, line 6).
As such, the specification objection is maintained.
Claim Rejections - 35 USC § 112(a) Written Description
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 30-34, 40-42, 44, 49-50, and 52-53 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 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 30 is drawn to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a topoisomerase I inhibitor and a bispecific antibody or antigen-binding fragments thereof that comprises a first antigen- binding site that specifically binds an extracellular part of epidermal growth factor receptor (EGFR) and a second antigen-binding site that specifically binds leucine-rich repeat- containing G-protein coupled receptor 5 (LGR5):wherein said first antigen-binding site comprises at least the complementarity determining region (CDR)1, CDR2, and CDR3 sequences of the heavy chain variable region MF3755 (SEQ ID NO: 89); wherein said second antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of the heavy chain variable region MF5816 (SEQ ID NO:107): and wherein the bispecific antibody comprises the CDR1, CDR2, and CDR3 sequences of a common light chain comprising SEQ ID NO:133.
Claim 31 is drawn to the method of claim 30, wherein the cancer is colorectal, pulmonary, gastrointestinal or ovarian cancer.
Claim 32 is drawn to the method of claim 31, wherein the cancer is colorectal cancer.
Claim 33 is drawn to the method of claim 30, wherein the bispecific antibody or antigen-binding fragments thereof and the topoisomerase I inhibitor are administered to the subject concurrently or sequentially.
Claim 34 is drawn to the method of claim 30, wherein the bispecific antibody or antigen-binding fragment thereof is administered to the subject prior to the topoisomerase I inhibitor.
Claim 40 is drawn to the method of claim 30, wherein the topoisomerase I inhibitor is camptothecin or a derivative thereof.
Claim 41 is drawn to the method of claim 30, wherein the topoisomerase I inhibitor is irinotecan or topotecan.
Claim 42 is drawn to the method of claim 30, wherein the bispecific antibody or antigen-binding fragments thereof is afucosylated.
Claim 44 is drawn to the method for inhibiting proliferation of a cell that expresses epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) comprising contacting the cell with a topoisomerase I inhibitor and a bispecific antibody or antigen-binding fragments thereof that comprises a first antigen- binding site that specifically binds an extracellular part of EGFR and a second antigen- binding site that specifically binds LGR5;wherein said first antigen-binding site comprises at least the complementarity determining region (CDR)1, CDR2, and CDR3 sequences of the heavy chain variable region MF3755 (SEQ ID NO: 89):wherein said second antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of the heavy chain variable region MF5816 (SEQ ID NO:107): and wherein the bispecific antibody comprises the CDR1, CDR2, and CDR3 sequences of a common light chain comprising SEQ ID NO:133.
Claim 49 is drawn to the method of claim 30, wherein the first antigen binding site comprises the variable heavy (VH) chain of MF3755, wherein the second antigen binding site comprises the VH chain of MF5816 and wherein both the first and second antigen binding sites comprise the common light chain comprising SEQ ID NO:133.
Claim 50 is drawn to the method of claim 44, wherein the first antigen binding site comprises the variable heavy (VH) chain of MF3755, wherein the second antigen binding site comprises the variable heavy (CH) chain of MF5816 and wherein both the first and second antigen binding sites comprise the common light chain comprising SEQ ID NO:133.
Claim 52 is drawn to the method of claim 41, wherein the topoisomerase I inhibitor is irinotecan.
Claim 53 is drawn to the method of claim 41, wherein the topoisomerase I inhibitor is topotecan.
The specification discloses of generating bispecific antibodies that target EGFR and LGR5 comprising heavy chain variable regions MF3755 and MF5816, and a common light chain, and including modifications for enhanced ADCC from afucosylation, among other LGR5 and EGFR combinations as depicted in Figure 9a (see pg. 39, lines 10-15). The specification discloses that preferred mutations to produce essentially only bispecific full length IgG molecules are amino acid substitutions at positions 351 and 366 in the first CH3 domain and amino acid substitutions at positions 351 and 368 in the second CH3 domain, or vice versa (see pg. 39, lines 17-32).
The specification discloses of the M005 model wherein 120 NOD-SCID mice were injected with human tumor cells derived from a CRC liver metastasis and contain mutations in the KRAS gene (KRAS G13D) and in the PIK3CA gene (PIK3CA 112_112del) (see pg. 41, lines 33-40). Treatments were initiated after at least 80% of animals had a primary tumor growing in the cecum (see Figure 3a). The mean tumor volume in mice treated with the bispecific EGFR/LGR5, comprising MF3755 and MF5816 alone, was lower than mice given vehicle, but not as low as that of mice treated with irinotecan alone; surprisingly, mice receiving the bispecific EGFR/LGR5, comprising MF3755 and MF5816 + irinotecan combination treatment had a lower tumor volume compared to all other groups of mice (see Figures 3b and 3c). After treatment release, the bispecific EGFR/LGR5, comprising MF3755 and MF5816 prolonged the tumor growth blocking effect of irinotecan as seen in the fold change in tumor volume (see Figure 4a). Furthermore, mice treated with the bispecific EGFR/LGR5, comprising MF3755 and MF5816 or irinotecan, either alone or in combination, had fewer metastases than untreated mice (see Figure 5a). The bispecific EGFR/LGR5, comprising MF3755 and MF5816 and irinotecan alone were able to delay primary tumor growth, but combination of the bispecific EGFR/LGR5, comprising MF3755 and MF5816 and irinotecan promote a superior response (see pg. 43, lines 24-27). After treatment release, combined treatment completely eliminated primary tumors in five out of five surviving mice and in terms of metastatic potential, the bispecific EGFR/LGR5, comprising MF3755 and MF5816 blocked the formation of distant metastases, as did irinotecan (see pg. 43, lines 27-36).
Lastly, the specification discloses of M001 model wherein mice were injected with human tumor cells originally derived from a CRC liver metastasis with mutations: KRAS G12D and PIK3CA-C420R (see pg. 42, lines 10-21; Figure 6a). The mean tumor volume in mice treated with the bispecific EGFR/LGR5, comprising MF3755 and MF5816 alone was very similar to that of mice treated with irinotecan alone; however, mice receiving the bispecific EGFR/LGR5, comprising MF3755 and MF5816 + irinotecan combination treatment had a lower tumor volume than any other group of mice (see Figure 6b, c). No toxicity was observed in mice receiving the combination of the bispecific EGFR/LGR5, comprising MF3755 and MF5816 + irinotecan (see Figure 7a). The bispecific EGFR/LGR5, comprising MF3755 and MF5816 and irinotecan alone were equally effective at delaying primary tumor growth, however, when administered together, the combined treatment appeared to be more effective than either agent given alone (see pg. 43, lines 38-42). In terms of metastatic potential, the bispecific EGFR/LGR5, comprising MF3755 and MF5816 blocked the formation of distant metastases, as did irinotecan; no metastases were seen in mice treated with combined irinotecan + the bispecific EGFR/LGR5, comprising MF3755 and MF5816 (see pg. 44, lines 10-14).
However, the specification fails to disclose that Applicant was in possession of the claimed invention. Specifically, the specification fails to disclose that Applicant was in possession of treating a large genus of cancers with a large genus of topoisomerase I inhibitors and claimed bispecific antibodies or fragments thereof. Claims 30 and 44 have been amended to introduce terms or phrases that are referenced parenthetically; however, the antibody clone names provided are arbitrary terms that as indicated in the instant specification, could have up to 15 amino acid variations in each chain. The clone name therefore does not identify a specific sequence.
Although the specification discloses bispecific EGFR/LGR5, comprising MF3755 and MF5816 and irinotecan treated CRC mouse models, the claims are not limited to this disease nor this topoisomerase I inhibitor, and are inclusive of any cancer treated with a large genus of topoisomerase I inhibitors and bispecific antibodies. This indicates that there are hundreds, if not thousands, of possible methods of treating cancer with a large genus of topoisomerase I inhibitors and bispecific antibodies encompassed by the claims. Thus, the claims encompass a vast genus of cancer-inhibitor treatments that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of topoisomerase I inhibitors and antibodies because, inter alia, the specification does not disclose a correlation between the necessary structure of the inhibitor and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Although the term antibody does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies/therapeutic agents and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of topoisomerase I inhibitors. The disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
The instant claims do not fully describe the structure of the topoisomerase I inhibitors to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of topoisomerase I inhibitors, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous topoisomerase I inhibitors had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of topoisomerase I inhibitors claimed only by a partial structure and functional characteristic(s). Thus the topoisomerase I inhibitors described by the instant claims encompasses an overly broad genus, and the functional outcome.
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). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of topoisomerase I inhibitors by the function of treating cancer or inhibiting proliferation of a cell. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed topoisomerase I inhibitors, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed antibodies and topoisomerase I inhibitors that are antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416; previously submitted with the Office Action mailed 08/11/2025) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2; previously submitted with the Office Action mailed 08/11/2025), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies inhibitors that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of inhibitors or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9; previously submitted with the Office Action mailed 08/11/2025), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990; previously submitted with the Office Action mailed 08/11/2025) who teach that replacement of a single lysine residue at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988; previously submitted with the Office Action mailed 08/11/2025) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98; previously submitted with the Office Action mailed 08/11/2025) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400; previously submitted with the Office Action mailed 08/11/2025) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668; previously submitted with the Office Action mailed 08/11/2025), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937; previously submitted with the Office Action mailed 08/11/2025). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
There is no disclosure relating similarity of any partial structure of the antibody to conservation of the immunogenic function. It is known for proteins, albeit not in all cases, that amino acid addition(s), substitution(s) or deletion(s) can destroy the function of the epitope or abolish its ability. This lack of predictability of the relationship between the protein sequence and the immunogenic epitope function is well documented by Mateu et al. (Mateu MG, et. al. Eur J Immunol. 1992 Jun;22(6):1385-9; previously submitted with the Office Action mailed 08/11/2025) and Greenspan et al. (Greenspan NS, Di Cera E. Defining epitopes: It's not as easy as it seems. Nat Biotechnol. 1999 Oct;17(10):936-7; previously submitted with the Office Action mailed 08/11/2025). The effects of these changes are largely unpredictable as to which ones have a significant effect versus not. Thus, the specification fails to adequately describe at least a substantial number of members of the immunogenic fragment genus to which the claims are based.
In summary, there are no known or disclosed peptide fragments having immunogenic activity other than the full-length polypeptides. As of the filing date, there was no known or disclosed correlation between a partial structure and immunogenic activity. Accordingly, one of skill in the art would not accept the disclosure of the full-length peptide as representative of fragments, homologs, or variants having immunogenic activity. Based on the lack of knowledge and predictability in the art, those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of immunogenic fragments based on the disclosure of the instant application. In conclusion, the specification, taken together with the pre-existing knowledge and the lack of predictability in the art, fails to satisfy the written description requirement of 35 U.S.C. 112, first paragraph, with respect to claims 288-291, 295-299, and 302-307.
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed antibodies and topoisomerase I inhibitors could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
Regarding topoisomerase I inhibitors that are small molecules, the prediction of binding to a target, much less the inhibitory activity, is highly unpredictable. According to Guido et al. (Curr Med Chem. 2008;15(1):37-46; previously submitted with the Office Action mailed 08/11/2025), accurately predicting the binding affinity of new drug candidates remains a major challenge in drug discovery (see page 37). There are a vast number of possible compounds that may bind any particular target, many of which have likely not been discovered. Relying on virtual screening also lends unpredictability to the art regarding identification of molecules that would be capable of the required functions of the instant claims. Guido et al. teach that there are two main complex issues with predicting activity for a small molecule: accurate structural modeling and/or correct prediction of activity (see page 40). As taught by Clark et al. (J. Med. Chem., 2014, 57 (12), pp 5023–5038; previously submitted with the Office Action mailed 08/11/2025), even when guided by structural data, developing selective structure-activity relationships has been challenging owing to the similarities of the enzymes (see page 5028). Therefore, it is impossible for one of skill in the art to predict that any particular encompassed small molecule therapeutic would function to inhibit a particular protein, especially a particular protein family member, or treat disease.
Regarding topoisomerase I inhibitors that are nucleic acid-based therapeutics, the efficacy of any possible DNA or RNA based therapeutic modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence the expression or function of any target. As taught by Aagaard et al. (Advanced Drug Delivery Reviews 59 (2007) 75–86; previously submitted with the Office Action mailed 08/11/2025), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems and therapeutics that are efficient at low doses (see page 79), the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses (see page 79), competition with cellular RNAi components (see page 83), the side effect of suppressing off targets (see page 80), and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al. (Leukemia and Lymphoma (1997) Vol. 24. pp. 267-281; previously submitted with the Office Action mailed 08/11/2025) teach that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three-dimensional RNA structures (see page 269), while DNA-targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins (see page 269). These references demonstrate that variation in RNA or DNA based therapeutics will often dramatically affect the biological activity and characteristics of the intended therapeutic. McKeague et al. (J Nucleic Acids. 2012;2012:748913. Epub 2012 Oct 24; previously submitted with the Office Action mailed 08/11/2025) teach that aptamers have particular challenges because unlike antibodies or molecular imprinted polymers, their tertiary structure is highly dependent on solution conditions and they are easily degraded in blood. Further, they have less chemical diversity than other antagonist molecules (see page 2), and have issues associated with determining the Kd measurements for a given molecule (see page 13).
Given the teachings of Aagaard et al, Warzocha et al, and McKeague et al, the claimed nucleic acid therapeutics could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed nucleic acid based therapeutic, such as oligonucleotide aptamers, RNAi molecules and antisense oligonucleotides, would function to decrease expression or function of a target gene or protein, or treat disease.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA or proteins, an adequate written description 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 (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all topoisomerase I inhibitors.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizardtech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed topoisomerase I inhibitors. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of topoisomerase I inhibitors as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Applicant’s Arguments
Applicant respectfully traverses the written description rejection as it may be applied to the amended claims presented herein (see pages 11 and 12 of the Remarks filed on 12/11/2025).
Applicant has amended claim 30 to recite “a bispecific antibody or antigen-binding fragments thereof that comprises a first antigen-binding site that specifically binds an extracellular part of EGFR and a second antigen-binding site that specifically binds LGR5; wherein said first antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of the heavy chain variable region MF3755 (SEQ ID NO: 89); wherein said second antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of the heavy chain variable region MF5816 (SEQ ID NO:107); and wherein the bispecific antibody comprises the CDR1, CDR2, and CDR3 sequences of a common light chain comprising SEQ ID NO:133”. Thus, the specification provides structural features common to all members of the claimed genus. Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co. 598 F.3d 1336 (Fed. Cir. 2010). Moreover, the specification provides adequate guidance as to the genus of topoisomerase I inhibitors (See, specification p. 12). Therefore, Applicant respectfully asserts that the specification clearly shows that Applicant possessed the claimed invention and requests that the rejection be reconsidered and withdrawn.
Response to Arguments
Applicant's arguments filed 12/11/2025 have been fully considered but they are not persuasive. Examiner acknowledges the amendments to the claims; specifically, Examiner acknowledges that claims 30 and 44 were amended to recite “a bispecific antibody or antigen-binding fragments thereof that comprises a first antigen-binding site that specifically binds an extracellular part of EGFR and a second antigen-binding site that specifically binds LGR5; wherein said first antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of the heavy chain variable region MF3755 (SEQ ID NO: 89); wherein said second antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of the heavy chain variable region MF5816 (SEQ ID NO:107); and wherein the bispecific antibody comprises the CDR1, CDR2, and CDR3 sequences of a common light chain comprising SEQ ID NO:133”. However, (1) the claims remain to inadequately describe the structure of the topoisomerase I inhibitor, (2) the specification nor the claims support that Applicant was in possession of treating all cancers or inhibiting proliferation in all cells with the claimed genus of topoisomerase I inhibitors and bispecific antibodies, and (3) the bispecific antibodies, even the CDRs, are still not properly described (see the newly added 112(b) rejection above). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Thus, the topoisomerase I inhibitor and antibodies recited in the claims are not limited to the species of recited in the specification.
While Applicant is entitled to use functional language in the description of claimed agents, according to MPEP 2163, an invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. This matches the facts here. The claims require specific functionality for the topoisomerase I inhibitor, but neither the instant disclosure, nor the art, provide description of the corresponding structure for that functionality or a representative number of species for the agents/components. In both the base claims and the dependent claims, for at least one agent/component in each claim, the claims only describe what the agent/component does, not what the agents/components are. Even when given possible sequences from which to select a fragment of a peptide that would inhibit topoisomerase I, the question remains about which one(s) of the encompassed peptides would actually perform the claimed function (i.e., treat all cancers). While methods to identify the peptides with the required function may be routine in the art, the fact that any experimentation is required to figure out exactly what is encompassed necessarily means that applicant has not sufficiently described the claimed subject matter.
There are thousands of possible topoisomerase I inhibitors and antibodies encompassed by the instant claims. One of skill in the art could not immediately envisage the encompassed species in each genus from the guidance provided in the instant specification and claims. Applicant has supplied a single species of topoisomerase I inhibitors (i.e., irinotecan), which in combination of MF3755 x MF5816 bispecific antibody treated CRC mouse models; however, the claims are not limited to this species. The claims encompass all topoisomerase I inhibitors. This encompasses an extremely broad genus of inhibitors with a specific function, for which no correlating structure is provided.
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 "merely by clearly describing one embodiment of the thing claimed." LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005). Describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene' s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described.").
As such, the written description rejection is maintained.
Claim Rejections - 35 USC § 112(a) Enablement
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 30-34, 42, 44, and 49-50 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating colorectal cancer comprising administering the bispecific EGFR/LGR5 antibody, comprising MF3755 and MF5816, and irinotecan, does not reasonably provide enablement for treating all cancers with any topoisomerase I inhibitor and a bispecific antibody that targets EGFR and LGR5 comprising the heavy chain CDRs of MF3755 and MF5816 and a common light chain comprising SEQ ID NO: 133. 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 claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement
requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S.
261, 270 (1916) which postured the question: is the experimentation needed to practice the
invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858
F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does
not use the term "undue experimentation," it has been interpreted to require that the claimed
invention be enabled so that any person skilled in the art can make and use the invention without
undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence
to support a determination that a disclosure does not satisfy the enablement requirement and whether
any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content
of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors most relevant for this rejection are: (A) the breadth of the claims; (B) the nature of the invention; (E) the level of predictability in the art; (F) the amount of direction provided by the inventor; (G) the existence of working examples; and (H) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In regard to Wands factors (A) and (B), the breadth of the claims needed to enable the invention
is determined by whether the scope of enablement provided to one skilled in the art by the disclosure is
commensurate with the scope of protection sought in the claims. AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003); In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). The propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one
skilled in the art could make and use the entire scope of the claimed invention without undue
experimentation.
The nature of the invention is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a topoisomerase I inhibitor and a bispecific antibody or antigen-binding fragments thereof that comprise a variable domain that binds an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5 comprising the heavy chain CDRs of MF3755 and MF5816 and a common light chain comprising SEQ ID NO: 133. Therefore, the nature of the invention is a biochemical case, where there is natural unpredictability in performance of certain species other than those specifically enumerated; see MPEP § 2163. Accordingly, it is the Office’s position that undue experimentation would be required to practice the functionality of the claimed method, with a reasonable expectation of success, because it would not be predictable from the disclosure of any one particular species may or may not work; see MPEP § 2164.03. Further, because the claims do not identify the topoisomerase inhibitors and bispecific antibodies by structure, it would require undue experimentation to determine what combination of inhibitors and antibodies will treat the vast genus of cancers.
In regard to Wands factors (C), (D), and (E), the state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains and provides evidence for the degree of predictability in the art; see MPEP § 2164.05(a). The claims encompass treating any cancer with any topoisomerase I inhibitor and any bispecific antibody or antigen-binding fragments thereof that comprise a variable domain that binds an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5 comprising the heavy chain CDRs of MF3755 and MF5816 and a common light chain comprising SEQ ID NO: 133. These cancers are highly heterogeneous at both the molecular and clinical level. Additionally, it is known in the art that cancer cells arising from different tissues differ in etiology and response to treatment. Heppner et al. (Cancer Metastasis Review 2:5-23; 1983; previously submitted with the Office Action mailed 08/11/2025) discuss the heterogeneity of tumors from different tissues, as well as the same tissue. A key point made by Heppner et al. is that tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult.
Additionally, Bally et al. (US Patent No. 5,595,756A, publication date: 01/21/1997; previously submitted with the Office Action mailed 08/11/2025) stated, "Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment limiting toxicities (See column 1).
Sporn et al. (Chemoprevention of Cancer, Carcinogenesis, Vol. 21 (2000), 525-530; previously submitted with the Office Action mailed 08/11/2025) teaches the magnitude of mortality of cancers and that mortalities are in fact still rising and that new approaches to a variety of different cancer are critically needed. Sporn et al. also teach that “given the genotype and phenotype heterogeneity of advanced malignant lesions as they occur in individual patients, one wonders just exactly what are the specific molecular and cellular targets for the putative cure.”
Furthermore, the art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al. (Cancer and Metastasis Reviews, 2000, 19: 167-172; previously submitted with the Office Action mailed 08/11/2025) indicate that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to permit screening of hybridoma supernatants…In vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality (see p. 167, left column, 1st paragraph).
Gura T (Science, 1997, 278(5340): 1041-1042, encloses 1-5; previously submitted with the Office Action mailed 08/11/2025) indicates that “the fundamental problem in drug discovery for cancer is that the model systems are not predictive at all” (see p. 1, 2nd paragraph). Furthermore, Gura indicates that the results of xenograft screening turned out to be not much better than those obtained with the original models, mainly because the xenograft rumors don’t behave like naturally occurring tumors in humans—they don’t spread to other tissues, for example (see p. 2, 4th paragraph). Further, when patient’s tumor cells in Petri dishes or culture flasks and monitor the cells’ responses to various anticancer treatments, they don’t work because the cells simply fail to divide in culture, and the results cannot tell a researcher how anticancer drugs will act in the body (see p. 3, 7th paragraph).
Furthermore, Jain RK (Scientific American, July 1994,58-65; previously submitted with the Office Action mailed 08/11/2025) indicates that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain (see p. 58, left most column, 1st paragraph). Further, Jain indicates that to eradicate tumors, the therapeutic agents must then disperse throughout the growths in concentrations high enough to eliminate every deadly cell…solid cancers frequently impose formidable barriers to such dispersion (see p. 58, bottom of the left most column continuing onto the top of the middle column). Jain indicates that there are 3 critical tasks that drugs must do to attack malignant cells in a tumor: 1) it has to make its way into a microscopic blood vessel lying near malignant cells in the tumor, 2) exit from the vessel into the surrounding matrix, and 3) migrate through the matrix to the cells. Unfortunately, tumors often develop in ways that hinder each of these steps (see p. 58, bottom of right most column). Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Hait (Nature Reviews/Drug Discovery, 2010, 9, pages 253-254; previously submitted with the Office Action mailed 08/11/2025) states that “The past three decades have seen spectacular advances in our understanding of the molecular and cellular biology of cancer. However, with a few notable exceptions, such as the treatment of chronic myeloid leukemia with imatinib, these advances have so far not been translated into major increases in long-term survival for many cancers. Furthermore, data suggest that the overall success rate for oncology products in clinical development is -10%, and the cost of bringing a new drug to market is over US$1 billion.” (see page 253, left column, the 1st paragraph). Hait further teaches “The anticancer drug discovery process often begins with a promising target; however, there are several reasons why the eventual outcome for a particular cancer target may be disappointing. For example, the role of the target in the pathogenesis of specific human malignancies may be incompletely understood, leading to disappointing results”, “First, many targets lie within signal transduction pathways that are altered in cancer, but, owing to the complex nature of these pathways, upstream or downstream components may make modulating the target of little or no value”; “Second, target overexpression is often overrated. There are some instances in which overexpression predicts response to treatment.”; and “Another confounding factor is that cancer is more than a disease of cancer cells, as alterations in somatic or germline genomes, or both, create susceptibilities to transformational changes in cells and in the microenvironment that ultimately cooperate to form a malignant tissue. The putative role of cancer stem cells in limiting the efficacy of cancer therapeutics is also an area of intense interest. Therefore, effective treatments may require understanding and disrupting the dependencies among the multiple cellular components of malignant tissues. Single nucleotide polymorphisms in genes responsible for drug metabolism can further complicate the picture by affecting drug pharmacokinetics; for example, as with the topoisomerase inhibitor irinotecan.”, for example, page 253, Section “Understanding the target in context”. Hait also teaches “Drug effects in preclinical cancer models often do not predict clinical results, as traditional subcutaneous xenografting of human cancer cell lines onto immunocompromised mice produces ‘tumors’ that fail to recapitulate key aspects of human malignancies such as invasion and metastasis. Several improvements have been made, including orthotopic implantation and use of mice with humanized hematopoietic and immune systems. Newer genetic mouse models can also allow analyses of tumor progression from in situ through locally advanced and, in certain cases, widespread metastatic disease. However, whether or not these models will more accurately predict drug activity against human cancer remains to be determined. Other alternatives, including three-dimensional tissue culture or xenografts of fresh human biopsy specimens onto immunocompromised mice, have the potential advantage of including the human microenvironment. However, these approaches have yet to prove their value relative to their cost.”, for example, page 253, Section “Predictive models”. Furthermore, Hait teaches that “It is now widely thought that biomarkers will drive a personalized approach to cancer drug development. The aim is that they will cut costs, decrease time to approval, and limit the number of patients who are exposed to potential toxicities without a reasonable chance of benefit — as exemplified by the development of imatinib and trastuzumab. However, recent attempts at repeating these successes in other cancer types have been less successful.”, for example, page 254, Section “Stratified/personalized medicine”.
The challenges facing cancer drug development are further confirmed and discussed in Gravanis et al. (Chin Clin Oncol, 2014, 3, pages 1 -5; previously submitted with the Office Action mailed 08/11/2025). Gravanis et al. teach “The generic mechanism of action for cytotoxics made the prediction of which tumor types might respond to them very difficult, if not impossible, and necessitated a ‘trial and error’ approach against many different types of tumors.” and “The most prominent change in oncology drug development in the last 20 years has been the shift from classic cytotoxics to drugs that affect signaling pathways implicated in cancer, which belong to the so called ‘targeted therapies’.”, for example, page 1, Section “From cytotoxics to targeted therapies: how far are we from truly personalized medicine?”. Gravanis et al. further teach “Although constantly progressing, an understanding of cancer biology is far from complete. The ability to develop new compounds or generate biological data predictive of the clinical situation relies on good quality basic research data, although the complexity and constantly evolving biology of the tumor may be to blame for the frequent non-reproducibility of research results. Systemic biology approaches of the -omic type still generate largely incomprehensible, mostly due to their volume, analytical data, few pieces of which are currently actionable/drug-g-able. Finally, animal models of cancer are similarly unable to predict the clinical situation (for example, page 3, right column, the 2nd paragraph).
Beans (PNAS 2018; 115(50): 12539-12543; previously submitted with the Office Action mailed 08/11/2025) teaches that across cancer types, 90% of cancer deaths are caused not by the primary tumor but by metastasis. Beans teaches that although some drugs may shrink metastases along with primary tumors, no existing drugs treat or prevent metastasis directly (See page 12540). Beans states “Without a targeted approach, metastatic tumors often reemerge. “We shrink them, we send them back to their residual state, and they reenact those survival functions and retention of regenerative powers that made them metastasis-initiating cells in the first place” (See page 12540). Beans teaches that one of the major scientific challenges of studying metastatic disease is that different forms of cancer seem to metastasize through different mechanisms and the same form of cancer may metastasize differently in different subsets of patients (See page 12542). Of note, Beans states “It’s unlikely that one researcher is going to find one pathway that proves to be the key to metastasis” (See page 12542). Beans also teaches that translating many findings into therapies also presents unique hurdles in that it is difficult to measure the effectiveness of the therapy. Secondary tumors are often minuscule, and therefore, measuring success by tumor shrinkage may not work. Measuring the incidence of metastasis after treatment is also more difficult (See page 12542).
Given Bally et al. teaching of treatment-limiting toxicities in clinical use; Sporn's teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype; Auerbach et al. teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response; Gura's teaching that the models are unpredictable; Jain's teaching that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain; both Hait and Gravanis et al teaching various challenges facing cancer drug development, such as an understanding of cancer biology is far from complete, drug effects in preclinical cancer models often do not predict clinical results and many others; and Beans teachings that the field is highly underdeveloped with regards to preventing and treating cancer metastasis; the cited references demonstrate that the treatment of cancer is highly unpredictable, if even possible for many cancers. In conclusion, the art provides evidence that heterogeneity in cancers can display unpredictability in response to the same treatment.
Furthermore, the art teaches the unpredictability of antibody-based cancer immunotherapy. Christiansen et al (Mol Cancer Ther, 2004, 3:1493-1501; previously submitted with the Office Action mailed 08/11/2025) teach numerous factors that inhibit successful therapeutic application of antibodies including low or heterogeneous expression of target antigens by tumor cells, high background expression of target antigen on normal cells, host antibody immune responses to the antibodies themselves, insufficient antitumor response after antibody binding, as well as significant physical barriers preventing antibody binding or delivery to a solid tumor mass, including the vascular endothelium, stromal barriers, high interstitial pressure, and epithelial barriers (abstract; p. 1493, col. 2; p. 1496, col. 1, last paragraph through p. 1498, col. 2). Topp et al (Journal of Controlled Release, 1998, 53:15-23; previously submitted with the Office Action mailed 08/11/2025) also teach the complications and unpredictability involved with treating tumors using antibody therapy. Topp et al teach that there are several barriers to successful delivery of antibody drugs to extravascular sites of action within target tissues: the antibody drugs must be absorbed into the blood stream, carried by the circulatory system to the capillaries in the target tissue, cross the capillary endothelial cells and the underlying basement membrane that supports the capillary structure and penetrate through the matrix of cells and extracellular components that comprises the tissue itself, bind to the cell surface receptor, initiate endocytosis, encounter possible drug degradation and drug release. Additional connective tissue barriers may also be encountered (p. 15, both columns; Figure 1). While some antibody drugs have been shown to be effective in vitro the results of clinical trials have been disappointing. The inability of the antibodies to penetrate the tumor mass could be a cause of this lack of clinical efficacy. Topp et al cautions against extrapolating in vitro results to in vivo therapy stating that the cell culture system has some limitations including a lack of well-developed extracellular matrix (“stroma”) that is present in many tumors. Normal components of tumor stroma include collagen, fibronectin and glycosaminoglycans (p. 21, col. 2). Given the unpredictable art of treating tumors in vivo using antibody therapy, one of skill in the art could not predictably treat colorectal in vivo comprising administering any topoisomerase I inhibitor as broadly claimed, other than the irinotecan from the working examples.
In regard to Wands factors (F), (G) and (H), the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech
Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004).
The claims are drawn to method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a topoisomerase I inhibitor and a bispecific antibody or antigen-binding fragments thereof that comprise a variable domain that binds an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5 comprising the heavy chain CDRs of MF3755 and MF5816 and a common light chain comprising SEQ ID NO: 133.
The working examples provided by Applicant do not demonstrate treating all cancers with a large genus of topoisomerase I inhibitors and antibodies, with the exception of colorectal cancer with the bispecific EGFR/LGR5 antibody, comprising MF3755 and MF5816 and a common light sequence, and irinotecan.
The specification discloses of the M005 model wherein 120 NOD-SCID mice were injected with human tumor cells derived from a CRC liver metastasis and contain mutations in the KRAS gene (KRAS G13D) and in the PIK3CA gene (PIK3CA 112_112del) (see pg. 41, lines 33-40). Treatments were initiated after at least 80% of animals had a primary tumor growing in the cecum (see Figure 3a). The mean tumor volume in mice treated with the bispecific EGFR/LGR5, comprising MF3755 and MF5816 alone, was lower than mice given vehicle, but not as low as that of mice treated with irinotecan alone; surprisingly, mice receiving the bispecific EGFR/LGR5, comprising MF3755 and MF5816 + irinotecan combination treatment had a lower tumor volume compared to all other groups of mice (see Figures 3b and 3c). After treatment release, the bispecific EGFR/LGR5, comprising MF3755 and MF5816 prolonged the tumor growth blocking effect of irinotecan as seen in the fold change in tumor volume (see Figure 4a). Furthermore, mice treated with the bispecific EGFR/LGR5, comprising MF3755 and MF5816 or irinotecan, either alone or in combination, had fewer metastases than untreated mice (see Figure 5a). The bispecific EGFR/LGR5, comprising MF3755 and MF5816 and irinotecan alone were able to delay primary tumor growth, but combination of the bispecific EGFR/LGR5, comprising MF3755 and MF5816 and irinotecan promote a superior response (see pg. 43, lines 24-27). After treatment release, combined treatment completely eliminated primary tumors in five out of five surviving mice and in terms of metastatic potential, the bispecific EGFR/LGR5, comprising MF3755 and MF5816 blocked the formation of distant metastases, as did irinotecan (see pg. 43, lines 27-36).
The specification also discloses of M001 model wherein mice were injected with human tumor cells originally derived from a CRC liver metastasis with mutations: KRAS G12D and PIK3CA-C420R (see pg. 42, lines 10-21; Figure 6a). The mean tumor volume in mice treated with the bispecific EGFR/LGR5, comprising MF3755 and MF5816 alone was very similar to that of mice treated with irinotecan alone; however, mice receiving the bispecific EGFR/LGR5, comprising MF3755 and MF5816 + irinotecan combination treatment had a lower tumor volume than any other group of mice (see Figure 6b, c). No toxicity was observed in mice receiving the combination of the bispecific EGFR/LGR5, comprising MF3755 and MF5816 + irinotecan (see Figure 7a). The bispecific EGFR/LGR5, comprising MF3755 and MF5816 and irinotecan alone were equally effective at delaying primary tumor growth, however, when administered together, the combined treatment appeared to be more effective than either agent given alone (see pg. 43, lines 38-42). In terms of metastatic potential, the bispecific EGFR/LGR5, comprising MF3755 and MF5816 blocked the formation of distant metastases, as did irinotecan; no metastases were seen in mice treated with combined irinotecan + the bispecific EGFR/LGR5, comprising MF3755 and MF5816 (see pg. 44, lines 10-14).
Because the specification only studied mouse models of one type of cancer, one cannot assume that the method of treating a vast variety of cancers will work similarly to the mouse models provided in the specification. In the absence of empirical determination, one skilled in the art would be subjected to undue experimentation to determine if the claimed method of treating any other type of cancer would result in therapeutic response as recited in the claims.
Applicant is reminded that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”. See Genentech, 108 F.3d 1361, 1366 (Fed. Cir. 1997).
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph.
Applicant’s Arguments
Applicant respectfully traverses the enablement rejection (see pages 12 and 13 of the Remarks filed on 12/11/2025).
Applicant has amended claim 30 to recite “a bispecific antibody or antigen-binding fragments thereof that comprises a first antigen-binding site that specifically binds an extracellular part of EGFR and a second antigen-binding site that specifically binds LGR5; wherein said first antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of the heavy chain variable region MF3755 (SEQ ID NO: 89); wherein said second antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of the heavy chain variable region MF5816 (SEQ ID NO:107); and wherein the bispecific antibody comprises the CDR1, CDR2, and CDR3 sequences of a common light chain comprising SEQ ID NO:133”.
The Office notes that the specification is enabling for treating colorectal cancer comprising administering a bispecific antibody comprising MF3755 and MF5816 and irinotecan (Office Action, p. 30). Applicant respectfully asserts that specification does enable a person of ordinary skill in the art (POSA) to make and use the invention commensurate with the scope of the claims presented herein without undue experimentation… Critically, however, case law does not require exhaustive testing of all embodiments (In re Wands (858 F.2d 731 (Fed. Cir. 1988)). In Amgen v. Sanofi (598 U.S. 594 (2023), the Court clarified that while a patent must enable the full scope of what is claimed, this does not mean every species must be individually disclosed. The key inquiry is whether the specification enables a POSA to make and use the invention across its claimed scope, not whether the Applicant has personally reduced every variant to practice. Based on the in vivo data showing efficacy of the claimed combination of bispecific antibody and topoisomerase inhibitor and the teachings of the specification, Applicant respectfully asserts that there is representative disclosure in the specification, that when combined with sufficient guidance from the exemplified data, that provides a skilled artisan the ability to practice the full scope of the claims without undue experimentation. Accordingly, Applicant respectfully asserts that the claimed invention is enabled and requests that the rejection be reconsidered and withdrawn.
Response to Arguments
Applicant's arguments filed 12/11/2025 have been fully considered but they are not persuasive. Examiner acknowledges the amendments to the claims; specifically, Examiner acknowledges that claims 30 and 44 were amended to recite “a bispecific antibody or antigen-binding fragments thereof that comprises a first antigen-binding site that specifically binds an extracellular part of EGFR and a second antigen-binding site that specifically binds LGR5; wherein said first antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of the heavy chain variable region MF3755 (SEQ ID NO: 89); wherein said second antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of the heavy chain variable region MF5816 (SEQ ID NO:107); and wherein the bispecific antibody comprises the CDR1, CDR2, and CDR3 sequences of a common light chain comprising SEQ ID NO:133”.
However, Examiner respectfully disagrees with Applicant’s interpretation of the Amgen v. Sanofi finding with respect to the instant invention. While The Court emphasized that an enabled specification need not disclose how to make and use every embodiment falling within a recited genus, this was in reference to the genus of antibodies and not a method of treating a large genus of cancers as presently claimed. As stated above, cancers are highly heterogeneous at both the molecular and clinical level and it is known in the art that cancer cells arising from different tissues differ in etiology and response to treatment. One cannot come to the conclusion that the working example provided in the specification will work similarly with the broad genus of cancers and topoisomerase I inhibitors as claimed. Further, claims 30 and 44 have been amended to introduce terms or phrases that are referenced parenthetically. The antibody clone names provided are arbitrary terms that as indicated in the instant specification, could have up to 15 amino acid variations in each chain. The clone name therefore does not identify a specific sequence. Thus the claims still claim an overly broad genus of antibodies. Thus, in the absence of empirical determination, one skilled in the art would be subjected to undue experimentation to determine if the claimed method of treating any other type of cancer would result in therapeutic response as recited in the claims.
Applicant is reminded that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”. See Genentech, 108 F.3d 1361, 1366 (Fed. Cir. 1997).
As such, the enablement rejection is maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Roovers et al and Prewett et al
Claims 30-34, 40-42, 44, 49-50, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Roovers et al (Cancer Res (2017) 77 (13_Supplement): 32; previously submitted in the restriction mailed on 04/17/2025) as evidenced by ChEMBL – Petosemtamab (www.ebi.ac.uk/chembl/explore/compound/CHEMBL4297781; accessed online 3/10/2026), and further in view of Prewett et al (Clin Cancer Res 2002;8:994-1003; previously submitted in the restriction mailed on 04/17/2025).
With respect to claims 30-32, 42, 44, and 49-50, Roovers et al disclose of a preclinical evaluation of MCLA-158, a bispecific antibody targeting LGR5 and EGFR, using patient-derived colon carcinoma organoids (see Title). A cohort of 32 genetically and transcriptionally annotated patient-derived colorectal cancer and normal colon organoids were used to functionally characterize responses to antibodies based on morphological changes with high content 3D imaging (see Methods). MCLA-158, an ADCC enhanced common light chain IgG1 bispecific antibody, binds in domain III of EGFR and in the N-Cap/1st LRR of LGR5, both ligand binding regions, however, only EGF binding was blocked by MCLA-158 (see Results). MCLA-158 demonstrated inhibitory activity in 74% of tumor organoids independent of KRAS mutational status but was not active on organoids of the cohort harboring both KRAS and PIK3CA mutations (see Results). MCLA-158 significantly inhibited the growth of the tumor compared to both control and cetuximab treatment (see Results). An initial evaluation of MCLA-158 toxicity in cynomolgus monkeys did not demonstrate any pathological finding after repeated dosing at 25 mg/kg (see Results). MCLA-158 demonstrates superior activity compared to reference antibodies in both in vitro and in vivo tumor organoid based assays regardless of KRAS status and was well tolerated in non-human primates (see Conclusions). While Roovers does not disclose of the sequence structure of MCLA-158, it is known that MCLA-158 comprises the heavy chain variable region MF3755 and MF5816, and a light chain as evidenced by ChEMBL. Thus, the MCLA-158 antibody of Roover comprises the sequences recited in the instant application.
Roovers et al fails to disclose of administering a topoisomerase I inhibitors, however this is remedied by Prewett et al.
With respect to claims 30, 33, 40-41, 44, and 52, Prewett et al disclose that anti-EGFR antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these in athymic mice (see Abstract). Prewett et al demonstrated the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice resulted in significantly inhibited growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (see Abstract).
Therefore, it would have been prima facie obvious to combine the teachings of Roovers and Prewett to develop the instant invention because Roovers et al disclose that their claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5 comprising the instant claimed sequences, and demonstrated inhibitory activity in patient-derived colon carcinoma organoids. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Therefore, it would have been prima facie obvious to combine the teachings of Roovers and Prewett to develop the instant invention because Roovers et al disclose that their claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5, and demonstrated inhibitory activity in patient-derived colon carcinoma organoids. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Thus, there is a reasonable expectation that administering the bispecific antibody and irinotecan would enhance the therapeutic activity within colorectal cancer patients.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering a bispecific antibody that targets EGFR and LGR5 in combination with irinotecan as taught in the references above, one would achieve a method for treating colorectal cancer.
While the art does not explicitly indicate administering the antibody prior to the topoisomerase I inhibitor as recited in claim 34, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, drug dosages, administration schedules, or treatment periods, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed drug dosages, administration schedules, and treatment period are akin to the variables discussed in the cited MPEP passage, because said drug dosages, administration schedules, and treatment period are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the claimed drug dosages, administration schedules, and treatment period, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to administration schedule which achieves a recognized result, such as drug toxicity and/or therapeutic benefit. Accordingly the recited administration schedule and treatment periods are result-effective variables that achieve a recognized result, such as drug toxicity and/or therapeutic benefit for a patient with a tumor, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum or workable ranges of said variables, the administration schedule/treatment period recited were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
Throsby et al and Prewett et al
Claims 30-34, 40-42, 44, 49-50, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Throsby et al (WO 2017/069628 A2; publication date: 04/27/2017; previously submitted with the Office Action mailed 08/11/2025), and further in view of Prewett et al (Clin Cancer Res 2002;8:994-1003; previously submitted in the restriction mailed on 04/17/2025).
In regard to clams 30-32, 42, 44, and 49-50, Throsby et al disclose of an antibody (PB10651) comprising a variable domain that binds EGFR and a variable domain that binds LGR5 wherein the VH chain of the variable domain that binds EGFR comprises the amino acid sequence of VH chain MF3755 and wherein the VH chain of the variable domain that binds LGR5 comprises the amino acid sequence of VH chain MF5816 (see pg. 44, lines 1-14). Throsby et al teach that the antibodies comprise of a common light chain wherein the common light chain comprises the human kappa light chain IgVĸ1-39*01/IGJĸ1*01 or a fragment or a functional equivalent thereof (see pg. 22, lines 1-30; pg. 57, lines 16-27). Throsby et al found that MF5816 combined with MF3755 in PB10651 adds another level of tumor inhibition by potently reducing tumoroid growth and development, observable by further loss of lumen formation, cell shrinkage and rounding up of the nuclei (see pg. 137, lines 28-31). Specifically, Throsby et al demonstrated that afucosylated PB10651 showed potent inhibitory effects at 10µg/mL test dose in 75% of the 24 different colon tumoroid models; 67% of the wells treated with PB10651 at 10µg/mL showed more than 50% growth reduction; 52% showed more than 50% growth reduction upon PB10651 treatment at 2µg/mL; and PB10651 outperformed cetuximab and the EGFR/TT reference antibody PB9919 (see pg. 138, lines 9-15; pg. 146, lines 4-20). Additionally, Figure 28A shows that treatment with a mixture of anti-LGR5 and anti-EGFR antibodies results in a less potent growth inhibition of tumoroids compared to treatment with the bispecific antibody PB10651 (see pg. 147, lines 1-12). Lastly, Throsby et al teach that the afucosylated PB10651, also referred to as MV1622, displayed significantly increased ADCC activity for all cell lines in combination with the high (V158) and low (F158) FcγRIIIa receptor variant (see pg. 150, lines 17-20). In colorectal patients, MV1622 presented strong tumoristatic activity (see Example 7).
However, Throsby et al fail to disclose of administering a topoisomerase I inhibitor. This is remedied by Prewett et al.
With respect to claims 30, 33, 40-41, 44, and 52, Prewett et al disclose that anti-EGFR antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these in athymic mice (see Abstract). Prewett et al demonstrated the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice resulted in significantly inhibited growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (see Abstract). Therefore, it would have been prima facie obvious to combine the teachings of Throsby and Prewett to develop the instant invention because Throsby et al disclose that their claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5, and demonstrated inhibitory activity in patient-derived colon and colorectal tumoroids. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Thus, there is a reasonable expectation that administering the bispecific antibody and irinotecan would enhance the therapeutic activity within colorectal cancer patients.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering a bispecific antibody that targets EGFR and LGR5 in combination with irinotecan as taught in the references above, one would achieve a method for treating colorectal cancer.
While the art does not explicitly indicate administering the antibody prior to the topoisomerase I inhibitor as recited in claim 34, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, drug dosages, administration schedules, or treatment periods, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed drug dosages, administration schedules, and treatment period are akin to the variables discussed in the cited MPEP passage, because said drug dosages, administration schedules, and treatment period are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the claimed drug dosages, administration schedules, and treatment period, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to administration schedule which achieves a recognized result, such as drug toxicity and/or therapeutic benefit. Accordingly the recited administration schedule and treatment periods are result-effective variables that achieve a recognized result, such as drug toxicity and/or therapeutic benefit for a patient with a tumor, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum or workable ranges of said variables, the administration schedule/treatment period recited were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
Applicant’s Arguments
Applicant respectfully requests that the 103 rejections be reconsidered and withdrawn (see pages 13-16).
With respect to the Roovers et al and Prewett rejection, the Office asserts that it would have been obvious to combine the teachings of Roovers and Prewett to arrive at the claimed invention because Roovers discloses the claimed MCLA-158 bispecific antibody and Prewett discloses that the anti-tumor activity of an anti-EGFR antibody is enhanced with the addition of irinotecan. In support of its assertion the Office cites to In re Kerkoven (205 USPQ 1069 (CCPA 1980). As an initial matter, Applicant respectfully asserts that the Office's reliance on Kerkhoven is misplaced. In Kerkhoven, the Federal Circuit held that claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents, a predictable process, were held to be prima facie obvious. Applicant respectfully asserts that claims to methods of treating cancer cannot be considered as predictable as claims to a process of preparing a spray-dried detergent. Applicant's assertion has been confirmed by the Federal Circuit. Moreover, the unpredictability of cancer treatment methods is highlighted by the 8 pages of analysis by the Office in rejecting the claims as not enabled. (See, Office Action, pp. 32- 39)… The Office's assertion that merely substituting one antibody for another is the type of unpredictability the court guards against. Thus, while the claimed elements "could" have been combined, that is not the legal standard, and that, as discussed above, in the medical arts "potential solutions are less likely to be genuinely predictable" as compared with other arts… In the present application, there are many potential combinations of antibodies and inhibitors useful for the treatment of cancer and there is no indication in the art for the combination of the claimed bispecific antibody and a topoisomerase I inhibitor without using Applicant's disclosure as a roadmap.
With respect to the Throsby and Prewett rejection, Applicant respectfully asserts that a POSA would not have arrived at the claimed invention with a reasonable expectation of success. It would not have been predictable that one could simply substitute a bispecific antibody for a monospecific antibody to successfully treat a subject as claimed.
Response to Arguments
Applicant's arguments filed 12/11/2025 have been fully considered but they are not persuasive.
It is acknowledged that in Applicant’s remarks, the teachings of Roovers and Prewett were not addressed. However, Examiner respectfully disagrees with Applicant’s assertion that the usage of In Kerkhoven was misplaced. While that case is in reference to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents that the Federal Court held to be prima facie obvious, there are similarities with the instant case. The instant claims have been amended to insufficiently describe the bispecific antibody. Specifically, because the claims reference the bispecific antibody with clone names, which could have up to 15 amino acid variations in each chain, the clone names do not reference a specific sequence. Therefore, there is a lack of enablement regarding the overly broad genus of antibodies and inhibitors treating a large genus of cancers compared to the teachings of the art in the rejection which presents an embodiment of the scope of enablement. Roovers et al disclose that their claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5 comprising the instant claimed sequences, and demonstrated inhibitory activity in patient-derived colon carcinoma organoids. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Therefore, it would have been prima facie obvious to combine the teachings of Roovers and Prewett to develop the instant invention because Roovers et al disclose that their claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5, and demonstrated inhibitory activity in patient-derived colon carcinoma organoids. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Thus, there is a reasonable expectation that administering the bispecific antibody of Roovers and irinotecan would enhance the therapeutic activity within colorectal cancer patients.
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).
It is acknowledged that in Applicant’s remarks, the teachings of Throsby and Prewett were not addressed. However, as stated above, Throsby et al disclose that their claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5, and demonstrated inhibitory activity in patient-derived colon and colorectal tumoroids. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Thus, there is a reasonable expectation that administering the bispecific antibody of Throsby and irinotecan would enhance the therapeutic activity within colorectal cancer patients.
As such, the 103 rejections are maintained.
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.
11,939,394
Claims 30-34, 40-41, 44, 49-50, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,939,394 B2 in view of Prewett et al (Clin Cancer Res 2002;8:994-1003; previously submitted in the restriction mailed on 04/17/2025).
The ‘394 patent is drawn to bispecific antibodies that comprise a variable domain that binds an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5 (see claims 1 and 7-30). Particularly, the ‘394 patent discloses of a bispecific antibody that comprises SEQ ID NO: 20 and SEQ ID NO: 26 (see claims 12 and 26) which shares 100% identity with instant SEQ ID NO: 89 and 107, respectively; and, consequently comprises the EGFR CDR sequences of SEQ ID Nos: 17, 19, and 21 and LGR5 CDR sequences of SEQ ID Nos: 69, 71, and 73. Additionally, the ‘394 patent discloses that the bispecific antibodies comprise a light chain variable domain comprising SEQ ID NO: 80 (see claim 2) which shares 100% identity with instant SEQ ID NO: 133.
The difference between the instant claims and the ‘394 patent is that the instant claims is drawn to a method of using a product whereas the ’394 patent is drawn to the product. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121. The ‘394 patent discloses of utilizing the claimed bispecific antibodies to treat colorectal patients (see Example 7).
Furthermore, with respect to administering a topoisomerase I inhibitor, Prewett et al disclose that anti-EGFR antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these in athymic mice (see Abstract). Prewett et al demonstrated the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice resulted in significantly inhibited growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (see Abstract). Therefore, it would have been prima facie obvious to combine the teachings of the ‘394 patent and Prewett to develop the instant invention because the ‘394 patent discloses that their claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5, and demonstrated inhibitory activity in patient-derived colon and colorectal tumoroids. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Thus, there is a reasonable expectation that administering the bispecific antibody and irinotecan would enhance the therapeutic activity within colorectal cancer patients.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering a bispecific antibody that targets EGFR and LGR5 in combination with irinotecan as taught in the references above, one would achieve a method for treating colorectal cancer.
While the art does not explicitly indicate administering the antibody prior to the topoisomerase I inhibitor as recited in claim 34, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, drug dosages, administration schedules, or treatment periods, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed drug dosages, administration schedules, and treatment period are akin to the variables discussed in the cited MPEP passage, because said drug dosages, administration schedules, and treatment period are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the claimed drug dosages, administration schedules, and treatment period, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to administration schedule which achieves a recognized result, such as drug toxicity and/or therapeutic benefit. Accordingly the recited administration schedule and treatment periods are result-effective variables that achieve a recognized result, such as drug toxicity and/or therapeutic benefit for a patient with a tumor, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum or workable ranges of said variables, the administration schedule/treatment period recited were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
17/921,042
Claims 30-34, 40-42, 44, 49-50, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31, 34, 37-41, 43-44, and 47-49 of copending Application No. 17/921,042 in view of Throsby et al (WO 2017/069628 A2; publication date: 04/27/2017) and Prewett et al (Clin Cancer Res 2002;8:994-1003; previously submitted in the restriction mailed on 04/17/2025).
With respect to instant claims 30-32, 42, 44, and 49-50, the ‘042 claims are drawn to a method of treating a cancer comprising administering to a human subject in need thereof a flat dose of 1500 mg of a bispecific antibody that comprises a first antigen- binding site that specifically binds an extracellular part of epidermal growth factor receptor (EGFR) and a second antigen-binding site that specifically binds leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5); wherein said first antigen-binding site comprises at least the complementarity determining region (CDR)1, CDR2, and CDR3 sequences of the heavy chain variable region MF3755 (SEQ ID NO:89) wherein said second antigen-binding site comprises at least the CDR1, CDR2, and CDR3 sequences of the heavy chain variable region MF5816 (SEQ ID NO:107); and wherein the bispecific antibody comprises the CDR1, CDR2, and CDR3 sequences of a common light chain comprising SEQ ID NO:133 (see claims 31 and 47). The ‘042 claims are drawn to the method of claim 31, wherein the antibody is ADCC enhanced (see claim 43). Lastly, the ‘042 claims are drawn to the method of claim 31, wherein the antibody is afucosylated (see claim 44).
The difference between the instant claims and the ‘042 claims is that the instant claims are drawn to a method of treating cancer wherein the method comprises administering a bispecific antibody and a topoisomerase I inhibitor. Additionally, the instant application discloses the bispecific antibody comprises a common light chain. This is remedied by Throsby and Prewett.
With respect to the common light chain, Throsby et al disclose of an antibody (PB10651) comprising a variable domain that binds EGFR and a variable domain that binds LGR5 wherein the VH chain of the variable domain that binds EGFR comprises the amino acid sequence of VH chain MF3755 and wherein the VH chain of the variable domain that binds LGR5 comprises the amino acid sequence of VH chain MF5816 (see pg. 44, lines 1-14). Throsby et al teach that the antibodies comprise of a common light chain wherein the common light chain comprises the human kappa light chain IgVĸ1-39*01/IGJĸ1*01 or a fragment or a functional equivalent thereof (see pg. 22, lines 1-30; pg. 57, lines 16-27). Throsby et al found that MF5816 combined with MF3755 in PB10651 adds another level of tumor inhibition by potently reducing tumoroid growth and development, observable by further loss of lumen formation, cell shrinkage and rounding up of the nuclei (see pg. 137, lines 28-31). Specifically, Throsby et al demonstrated that afucosylated PB10651 showed potent inhibitory effects at 10µg/mL test dose in 75% of the 24 different colon tumoroid models; 67% of the wells treated with PB10651 at 10µg/mL showed more than 50% growth reduction; 52% showed more than 50% growth reduction upon PB10651 treatment at 2µg/mL; and PB10651 outperformed cetuximab and the EGFR/TT reference antibody PB9919 (see pg. 138, lines 9-15; pg. 146, lines 4-20). Additionally, Figure 28A shows that treatment with a mixture of anti-LGR5 and anti-EGFR antibodies results in a less potent growth inhibition of tumoroids compared to treatment with the bispecific antibody PB10651 (see pg. 147, lines 1-12). Lastly, Throsby et al teach that the afucosylated PB10651, also referred to as MV1622, displayed significantly increased ADCC activity for all cell lines in combination with the high (V158) and low (F158) FcγRIIIa receptor variant (see pg. 150, lines 17-20). In colorectal patients, MV1622 presented strong tumoristatic activity (see Example 7).
Further, with respect to administering a topoisomerase I inhibitor, Prewett et al disclose that anti-EGFR antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these in athymic mice (see Abstract). Prewett et al demonstrated the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice resulted in significantly inhibited growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (see Abstract). Therefore, it would have been prima facie obvious to combine the teachings of the ‘042 application, Throsby, and Prewett to develop the instant invention because Throsby et al disclose that their claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5, and demonstrated inhibitory activity in patient-derived colon and colorectal tumoroids. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Thus, there is a reasonable expectation that administering the bispecific antibody and irinotecan would enhance the therapeutic activity within colorectal cancer patients.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering a bispecific antibody that targets EGFR and LGR5 in combination with irinotecan as taught in the references above, one would achieve a method for treating cancer.
While the art does not explicitly indicate administering the antibody prior to the topoisomerase I inhibitor as recited in claim 34, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, drug dosages, administration schedules, or treatment periods, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed drug dosages, administration schedules, and treatment period are akin to the variables discussed in the cited MPEP passage, because said drug dosages, administration schedules, and treatment period are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the claimed drug dosages, administration schedules, and treatment period, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to administration schedule which achieves a recognized result, such as drug toxicity and/or therapeutic benefit. Accordingly the recited administration schedule and treatment periods are result-effective variables that achieve a recognized result, such as drug toxicity and/or therapeutic benefit for a patient with a tumor, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum or workable ranges of said variables, the administration schedule/treatment period recited were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
This is a provisional nonstatutory double patenting rejection.
18/257,528
Claims 30, 33-34, 40-42, 44, 49-50, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20-33 of copending Application No. 18/257,528 in view of Prewett et al (Clin Cancer Res 2002;8:994-1003; previously submitted in the restriction mailed on 04/17/2025).
With respect to instant claims 30, 42, 44, and 49-50, the ‘528 claims are drawn to a method of treating head and neck cancer in a subject in need thereof, comprising administering to the subject an antibody or antigen-binding fragment thereof comprising a variable domain that binds an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5,wherein the subject is administered a flat dose of 1500 mg of the antibody or an equivalent amount of the antigen-binding fragment thereof, wherein the variable domain that binds an extracellular part of EGFR comprises a heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences of a variable region selected from the group consisting of MF3370 (SEQ ID NO: 3); MF3755 (SEQ ID NO: 4); MF4280 (SEQ ID NO: 5) or MF4289 (SEQ ID NO: 6), wherein the variable domain that binds an extracellular part of LGR5 comprises a heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences of a variable region selected from the group consisting of MF5790 (SEQ ID NO: 7); MF5803 (SEQ ID NO: 8); MF5805 (SEQ ID NO: 9); MF5808 (SEQ ID NO: 10); MF5809 (SEQ ID NO: 11); MF5814 (SEQ ID NO: 12); MF5816 (SEQ ID NO: 13); MF5817 (SEQ ID NO: 14); or MF5818 (SEQ ID NO: 15) and, wherein both variable domains comprise CDR1, CDR2 and CDR3 regions of the light chain variable region of SEQ ID NO: 122 (see claims 20-31). SEQ ID Nos: 4, 13, and 122 share 100% identity with instant SEQ ID Nos: 89, 107, and 133, respectively. Additionally, the ‘528 claims are drawn to the method of claim 20, wherein the antibody is ADCC enhanced (see claim 32). Lastly, the ‘528 claims are drawn to the method of claim 20, wherein the antibody is afucosylated (see claim 33).
The difference between the instant claims and the ‘528 application is that the instant claims are drawn to a method of treating cancer wherein the method comprises administering the claimed bispecific antibody and a topoisomerase I inhibitor.
However, Prewett et al disclose that anti-EGFR antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these in athymic mice (see Abstract). Prewett et al demonstrated the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice resulted in significantly inhibited growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (see Abstract). Therefore, it would have been prima facie obvious to combine the teachings of the ‘528 application and Prewett to develop the instant invention because the ‘528 application discloses that their claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Thus, there is a reasonable expectation that administering the bispecific antibody and irinotecan would enhance the therapeutic activity within cancer patients.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering a bispecific antibody that targets EGFR and LGR5 in combination with irinotecan as taught in the references above, one would achieve a method for treating cancer.
While the art does not explicitly indicate administering the antibody prior to the topoisomerase I inhibitor as recited in claim 34, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, drug dosages, administration schedules, or treatment periods, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed drug dosages, administration schedules, and treatment period are akin to the variables discussed in the cited MPEP passage, because said drug dosages, administration schedules, and treatment period are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the claimed drug dosages, administration schedules, and treatment period, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to administration schedule which achieves a recognized result, such as drug toxicity and/or therapeutic benefit. Accordingly the recited administration schedule and treatment periods are result-effective variables that achieve a recognized result, such as drug toxicity and/or therapeutic benefit for a patient with a tumor, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum or workable ranges of said variables, the administration schedule/treatment period recited were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
This is a provisional nonstatutory double patenting rejection.
18/268,168
Claims 30-34, 40-42, 44, 49-50, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 42-70 of copending Application No. 18/268,168 in view of Throsby et al (WO 2017/069628 A2; publication date: 04/27/2017) and Prewett et al (Clin Cancer Res 2002;8:994-1003; previously submitted in the restriction mailed on 04/17/2025).
The ‘168 claims are drawn to a pharmaceutical composition comprising: a multispecific antibody, functional part, or derivative thereof, comprising a first binding domain binding to Epidermal Growth Factor Receptor (EGFR) and a second binding domain binding to Leucine-rich repeat-containing G protein-coupled Receptor 5 (LGR5); a buffer system comprising a histidine buffer, a citrate buffer, or both; a sugar component; and a non-ionic surfactant (see claims 42-70). The ‘168 claims are drawn to the pharmaceutical composition of claim 42, wherein the antibody comprises an EGFR binding domain comprising a heavy chain variable region (VH) that comprises the sequence of the VH chain of MF3370, MF3755, MF4280, or MF4289, or wherein the antibody comprises an LGR5 binding domain comprising a heavy chain variable region that comprises the sequence of the VH chain of MF5790, MF5803, MF5805, MF5808, MF5809, MF5814, MF5816, MF5817, or IF5818 (see claims 55-63). Specifically, SEQ ID Nos: 5, 41, and 53 share 100% identity with instant SEQ ID Nos: 89, 107, and 133, respectively.
The difference between the instant claims and the ‘168 application is that the instant claims is drawn to a method of using a product whereas the ‘168 application is drawn to the product. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121.
Throsby et al disclose of an antibody (PB10651) comprising a variable domain that binds EGFR and a variable domain that binds LGR5 wherein the VH chain of the variable domain that binds EGFR comprises the amino acid sequence of VH chain MF3755 and wherein the VH chain of the variable domain that binds LGR5 comprises the amino acid sequence of VH chain MF5816 (see pg. 44, lines 1-14). Throsby et al teach that the antibodies comprise of a common light chain wherein the common light chain comprises the human kappa light chain IgVĸ1-39*01/IGJĸ1*01 or a fragment or a functional equivalent thereof (see pg. 22, lines 1-30; pg. 57, lines 16-27). Throsby et al found that MF5816 combined with MF3755 in PB10651 adds another level of tumor inhibition by potently reducing tumoroid growth and development, observable by further loss of lumen formation, cell shrinkage and rounding up of the nuclei (see pg. 137, lines 28-31). Specifically, Throsby et al demonstrated that afucosylated PB10651 showed potent inhibitory effects at 10µg/mL test dose in 75% of the 24 different colon tumoroid models; 67% of the wells treated with PB10651 at 10µg/mL showed more than 50% growth reduction; 52% showed more than 50% growth reduction upon PB10651 treatment at 2µg/mL; and PB10651 outperformed cetuximab and the EGFR/TT reference antibody PB9919 (see pg. 138, lines 9-15; pg. 146, lines 4-20). Additionally, Figure 28A shows that treatment with a mixture of anti-LGR5 and anti-EGFR antibodies results in a less potent growth inhibition of tumoroids compared to treatment with the bispecific antibody PB10651 (see pg. 147, lines 1-12). Lastly, Throsby et al teach that the afucosylated PB10651, also referred to as MV1622, displayed significantly increased ADCC activity for all cell lines in combination with the high (V158) and low (F158) FcγRIIIa receptor variant (see pg. 150, lines 17-20). In colorectal patients, MV1622 presented strong tumoristatic activity (see Example 7).
Furthermore, with respect to administering a topoisomerase I inhibitor, Prewett et al disclose that anti-EGFR antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these in athymic mice (see Abstract). Prewett et al demonstrated the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice resulted in significantly inhibited growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (see Abstract). Therefore, it would have been prima facie obvious to combine the teachings of the ‘168 application, Throsby, and Prewett to develop the instant invention because the ‘168 application and Throsby discloses that their claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5, and demonstrated inhibitory activity in patient-derived colon and colorectal tumoroids. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Thus, there is a reasonable expectation that administering the bispecific antibody and irinotecan would enhance the therapeutic activity within colorectal cancer patients.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering a bispecific antibody that targets EGFR and LGR5 in combination with irinotecan as taught in the references above, one would achieve a method for treating colorectal cancer.
While the art does not explicitly indicate administering the antibody prior to the topoisomerase I inhibitor as recited in claim 34, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, drug dosages, administration schedules, or treatment periods, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed drug dosages, administration schedules, and treatment period are akin to the variables discussed in the cited MPEP passage, because said drug dosages, administration schedules, and treatment period are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the claimed drug dosages, administration schedules, and treatment period, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to administration schedule which achieves a recognized result, such as drug toxicity and/or therapeutic benefit. Accordingly the recited administration schedule and treatment periods are result-effective variables that achieve a recognized result, such as drug toxicity and/or therapeutic benefit for a patient with a tumor, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum or workable ranges of said variables, the administration schedule/treatment period recited were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
This is a provisional nonstatutory double patenting rejection.
18/431,642
Claims 30-34, 40-42, 44, 49-50, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29-59 of copending Application No. 18/431,642 in view of Prewett et al (Clin Cancer Res 2002;8:994-1003; previously submitted in the restriction mailed on 04/17/2025).
The ‘642 claims are drawn to a method for the treatment of an individual that has a cancer, the method comprising administering a bispecific antibody to said individual, wherein said bispecific antibodies that comprise a variable domain that binds an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5 (see claims 29-59). Particularly, the ‘642 claims disclose of a bispecific antibody that comprises SEQ ID NO: 20 and SEQ ID NO: 26 (see claims 37 and 49) which shares 100% identity with instant SEQ ID NO: 89 and 107, respectively; and, consequently comprises the EGFR CDR sequences of SEQ ID Nos: 17, 19, and 21 and LGR5 CDR sequences of SEQ ID Nos: 69, 71, and 73. Additionally, the ‘642 claims disclose that the bispecific antibodies comprise a light chain variable domain comprising SEQ ID NO: 80 (see claim 31) which shares 100% identity with instant SEQ ID NO: 133.
The difference between the instant claims and the ‘642 application is that the instant claims is drawn to a method of treating cancer comprising administering a topoisomerase I inhibitor and the bispecific antibody. However, this is remedied by Prewett et al.
Prewett et al disclose that anti-EGFR antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these in athymic mice (see Abstract). Prewett et al demonstrated the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice resulted in significantly inhibited growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (see Abstract). Therefore, it would have been prima facie obvious to combine the teachings of the ‘642 application and Prewett to develop the instant invention because the ‘642 application discloses of a method of treating cancer comprising administering the claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Thus, there is a reasonable expectation that administering the bispecific antibody and irinotecan would enhance the therapeutic activity within colorectal cancer patients.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering a bispecific antibody that targets EGFR and LGR5 in combination with irinotecan as taught in the references above, one would achieve a method for treating colorectal cancer.
While the art does not explicitly indicate administering the antibody prior to the topoisomerase I inhibitor as recited in claim 34, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, drug dosages, administration schedules, or treatment periods, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed drug dosages, administration schedules, and treatment period are akin to the variables discussed in the cited MPEP passage, because said drug dosages, administration schedules, and treatment period are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the claimed drug dosages, administration schedules, and treatment period, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to administration schedule which achieves a recognized result, such as drug toxicity and/or therapeutic benefit. Accordingly the recited administration schedule and treatment periods are result-effective variables that achieve a recognized result, such as drug toxicity and/or therapeutic benefit for a patient with a tumor, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum or workable ranges of said variables, the administration schedule/treatment period recited were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
This is a provisional nonstatutory double patenting rejection.
18/694,252
Claims 30-34, 40-42, 44, 49-50, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3-7, 9-16, 18, 20, 23, 27, 31, and 36-42 of copending Application No. 18/694,252 in view of Prewett et al (Clin Cancer Res 2002;8:994-1003; previously submitted in the restriction mailed on 04/17/2025).
The ‘252 claims are drawn to a method of treating a subject having an EGFR expressing cancer, wherein said subject has progressed after having received prior treatment with an immune checkpoint inhibitor, the method comprising providing the subject with an effective amount of an antibody or functional part thereof that comprises a first variable domain that binds an extracellular part of EGFR comprising a heavy chain variable region that comprises the CDR1, CDR2 and CDR3 sequences of MF3755 (SEQ ID NO:4) and a second variable domain comprising a heavy chain variable region that comprises the CDR1, CDR2 and CDR3 sequences of MF5816 (SEQ ID NO:13) (see claims 3-7, 9-16, 18, 20, 23, 27, and 31). SEQ ID Nos: 4 and 13 share 100% identity with instant SEQ ID Nos: 89 and 107, respectively. Additionally, the ‘252 claims are drawn to the method of claim 3, wherein the first and second variable domains comprise a light chain variable region comprising the LCDR1 amino acid sequence QSISSY, the LCDR2 amino acid sequence AAS, and the LCDR3 amino acid sequence QQSYSTPPT (see claim 37). The ‘252 claims are drawn to the method of claim 37, wherein the first and second variable domains comprise a light chain variable region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 122 (see claims 38-40). SEQ ID NO: 122 shares 100% identity with instant SEQ ID NO: 133.
The difference between the instant claims and the ‘252 application is that the instant claims are drawn to a method of treating cancer wherein the method comprises administering a topoisomerase I inhibitor and the bispecific antibody. This is remedied by Prewett.
Prewett et al disclose that anti-EGFR antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these in athymic mice (see Abstract). Prewett et al demonstrated the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice resulted in significantly inhibited growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (see Abstract). Therefore, it would have been prima facie obvious to combine the teachings of the ‘252 application and Prewett to develop the instant invention because the ‘252 application discloses of a method of treating cancer comprising administering the claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Thus, there is a reasonable expectation that administering the bispecific antibody and irinotecan would enhance the therapeutic activity within cancer patients.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering a bispecific antibody that targets EGFR and LGR5 in combination with irinotecan as taught in the references above, one would achieve a method for treating cancer.
While the art does not explicitly indicate administering the antibody prior to the topoisomerase I inhibitor as recited in claim 34, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, drug dosages, administration schedules, or treatment periods, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed drug dosages, administration schedules, and treatment period are akin to the variables discussed in the cited MPEP passage, because said drug dosages, administration schedules, and treatment period are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the claimed drug dosages, administration schedules, and treatment period, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to administration schedule which achieves a recognized result, such as drug toxicity and/or therapeutic benefit. Accordingly the recited administration schedule and treatment periods are result-effective variables that achieve a recognized result, such as drug toxicity and/or therapeutic benefit for a patient with a tumor, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum or workable ranges of said variables, the administration schedule/treatment period recited were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
This is a provisional nonstatutory double patenting rejection.
Applicant’s Arguments
Applicant respectfully traverses the rejection as it may be applied to the amended claims presented herein. (see pages 16 and 17 of the Remarks filed 12/11/2025)
The claims 1-30 of '394 patent are directed to a series of bispecific antibodies that bind EGFR and LGR5. There is no teaching or suggestion to combine the antibodies with a topoisomerase I inhibitor in a therapeutic method to treat cancer. Prewitt does not provide a reasonable expectation of success in arriving at the claimed invention for at least the reasons noted above. Accordingly, Applicant respectfully requests that the rejection be reconsidered and withdrawn.
None of the cited patent applications teach or suggest administering an antibody that binds EGFR and LGR5 in combination with a topoisomerase I inhibitor in a method of treating cancer. Prewitt does not provide a reasonable expectation of success in arriving at the claimed invention for at least the reasons noted above. Moreover, each of the above-cited rejections are provisional rejections. Applicant respectfully believes each of above rejections has been overcome and thus requests that the instant application be allowed to pass to allowance in accordance with M.P.E.P. 804(B)(1)(b)(i).
Response to Arguments
Applicant's arguments filed 12/11/2025 have been fully considered but they are not persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the ‘394 patent discloses of utilizing the claimed bispecific antibodies to treat colorectal patients (see Example 7). Additionally, Prewett et al disclose that anti-EGFR antibody IMC-C225 can inhibit the growth of human colon carcinoma tumor cells in vitro and xenografts of these in athymic mice (see Abstract). Prewett et al demonstrated the in vivo activity of IMC-C225 combined with the topoisomerase I inhibitor irinotecan (CPT-11) using two models of human colorectal carcinoma in nude mice resulted in significantly inhibited growth of established DLD-1 and HT-29 tumors compared with either CPT-11 or IMC-C225 monotherapy (see Abstract). The Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121. Furthermore, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Therefore, it would have been prima facie obvious to combine the teachings of the ‘394 patent and Prewett to develop the instant invention because the ‘394 patent discloses that their claimed bispecific antibody binds to an extracellular part of EGFR and a variable domain that binds an extracellular part of LGR5, and demonstrated inhibitory activity in patient-derived colon and colorectal tumoroids. Further, Prewett et al disclose that the antitumor activity of anti-EGFR antibodies is enhanced with the addition of a topoisomerase I inhibitor such as irinotecan. Thus, there is a reasonable expectation that administering the bispecific antibody and irinotecan would enhance the therapeutic activity within colorectal cancer patients.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the ‘042 application, ‘528 application, ‘642 application, and ‘252 application are all drawn to a method of treating cancer comprising administering the claimed bispecific antibody; and, the ‘168 application is drawn to a pharmaceutical composition comprising the claimed bispecific antibody. While the US patent applications may not teach of administering a topoisomerase I inhibitor, it was known in the art that irinotecan enhanced antitumor activity of anti-EGFR antibodies as taught by Prewett. Furthermore, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Thus, there is a reasonable expectation that administering the bispecific antibody and irinotecan would enhance the therapeutic activity within colorectal cancer patients.
As such, the double patenting rejections are maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674