Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amendment filed September 25, 2025 in response to the Office Action of June 26, 2025 is acknowledged and has been entered.
Claims 1-9 and 13 have been amended.
Claim 14 has been added.
Claims 1-14 are pending and under consideration.
Priority
It is acknowledged that this application is a continuation application of U.S. Patent Appl. No. 16/499,623 filed September 30, 2019, which is a national phase application of PCT/US2018/025470, filed March 30, 2018, which claims the benefit of priority to U.S. Provisional Patent Appl. No. 62/479,768, filed March 31, 2017.
Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more amended claims of this application. Examiner has established a priority date of October 4, 2023 for amended claims 5, 8, 9 because the claims as currently constituted recite:
“the method of claim 2, further comprising detecting the expression of avb3 expression in a sample isolated from the subject following administration of the RTK inhibitor” (claim 5);
“the method of claim 2, further comprising detecting the concentration of tumor associated macrophages in the subject following administration of the RTK inhibitor” (claim 8);
“the method of claim 1, wherein administration of the RTK inhibitor increases the concentration of tumor associated macrophages (TAM)” (claim 9).
However, a review of the parent applications does not reveal the newly added limitations in the claimed methods (also see 112(a) NEW MATTER rejection below). Applicant is invited to submit evidence pointing to the serial number, page and line where support can be found establishing an earlier priority date.
It is noted that examiner has established a priority date of October 4, 2023 for original claim 12 in the previous Office Action of June 25, 2025. That priority date for claim 12 is maintained.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that use the word “means” or “step” but are nonetheless not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph because the claim limitation(s) recite(s) sufficient structure, materials, or acts to entirely perform the recited function. Such claim limitation(s) is/are: “means for binding to a human avb3 integrin polypeptide” in claim 1; and “means for binding to a human macrophage” in claim 13.
Because this/these claim limitation(s) is/are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are not being interpreted to cover only the corresponding structure, material, or acts described in the specification as performing the claimed function, and equivalents thereof.
Specifically, with regard to the "three prong test", both claims recite "means" and thus prong "A" is satisfied. Further, both claims recite the functional language of "for binding to a human avb3 integrin polypeptide" (claim 1); or “for binding to a human macrophage” (claim 13) and thus satisfy prong B. However, the claims do not satisfy prong C which requires that "the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function." This is because claim 1 modifies the "means for binding" to necessarily have the structure of being an antibody; claim 13 modifies the “mean for binding” to necessarily have the structure of being an Fc domain of an antibody. Thus, the claims do provide structural limitations concerning the "means" that is binding a human avb3 polypeptide (claim 1) or binding a human macrophage (claim 13) so that it is not generic.
For example, the natural ligand for the human avb3 integrin is vitronectin (as evidenced by paragraph [0118] of instant publication US 2024/0067733 A1, of record). However, vitronectin cannot serve as a "means for binding a human avb3 integrin polypeptide” (even though it very clearly does bind avb3) because it is not an antibody as is required by claim 1. Therefore, it is clear that the recited "means" is modified by the structure of having to be an antibody rather than being a "generic" means with no structural limitations as 35 USC 112(f) requires.
For claim 13, different proteins bind to human macrophage through various mechanisms, including surface receptors like Toll-like receptors (TLRs). TLRs are a major class of surface receptor on macrophage. OmpA, for example, is a conserved outer membrane protein from bacteria that binds to and activates human macrophage (see Soulas et al., J Immunol. 165 (5): 2335-2340, Publication Year: 2000, Abstract). However, OmpA cannot serve as a "means for binding a human macrophage” even though it very clearly does bind human macrophage because it is not an Fc domain of an antibody as is required by claim 13. Therefore, it is clear that the recited "means" is modified by the structure of having to be an Fc domain of an antibody rather than being a "generic" means with no structural limitations as 35 USC 112(f) requires.
Because this/these claim limitation(s) is/are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are not being interpreted to cover only the corresponding structure, material, or acts described in the specification as performing the claimed function, and equivalents thereof.
If applicant intends to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to remove the structure, materials, or acts that performs the claimed function; or (2) present a sufficient showing that the claim limitation(s) does/do not recite sufficient structure, materials, or acts to perform the claimed function.
MAINTAINED OBJECTION
Specification
The use of the term GEMZARTM, ABRAXANETM, TARCEVATM, TYKERBTM, or ERBIYUXTM, 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.
MAINTAINED/MODIFIED REJECTION
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, and 4-14 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. This is a WRITTEN DESCRIPTION rejection.
The rejected claims are drawn to a method for treating a receptor tyrosine kinase (RTK) inhibitor-resistant avb3 polypeptide-expressing epithelial cancer in a subject in need thereof, comprising: administering an RTK inhibitor; and an effective amount of an anti-avb3 integrin antibody comprising a means for binding to a human avb3 integrin polypeptide expressed on the receptor tyrosine kinase (RTK) inhibitor-resistant avb3 polypeptide-expressing cancer. Applicant has broadly claimed methods of administering anti-avb3 antibodies in combination with an RTK inhibitor to treat RTK inhibitor-resistant avb3+ epithelial cell cancer. Given BRI, the claims encompass a broad genus of anti-avb3 antibodies which can bind the avb3 via a “means for binding” to cell surface-expressed avb3 polypeptide. Note that as discussed above in this office action under 35 USC 112(f), the recited “means for binding” is structurally modified by the requirement that it be an antibody. This means that the term is NOT being interpreted to cover only the corresponding structure, material, or acts described in the specification as performing the claimed function, and equivalents thereof. The instant specification disclose only anti-avb3 antibody (LM609) can treat an erlotinib (an EGFR inhibitor) resistant cancers (see [0125] and Example 1 of instant publication US 2024/0067733 A1, of record). Thus, the specification lacks written description support for the broadly claimed genera.
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, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. (See Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001, especially page 1106 3rd column). A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. MPEP 2163 II.A.3a.ii.
Regarding the broad genus of anti-avb3 integrin antibodies comprising a means for binding to a human avb3 integrin polypeptide expressed on the receptor tyrosine kinase (RTK) inhibitor-resistant avb3 polypeptide-expressing cancer, given BRI, the antibodies can be monoclonal antibodies or polyclonal antibodies (known or yet to be discovered) with different origins (including human antibodies, as evidenced by claim 11); the antibodies can bind to different epitope of avb3.
MPEP 2163 II A 3(a) states: Disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope. Even a single point mutation in HCDR1 region could lead to antibody lose its binding activity (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024, see Abstract, of record). Thus, the specific antibodies disclosed by the specification would not tell structure of other antibodies to avb3 or variants of thereof.
In the instant case, the specification and prior art (see 103 rejection below) discloses a few anti-avb3 antibodies (see antibodies listed in claim 3), and only antibodies derived from LM609 including Vitaxin, Vitaxin Fc variants show the activity for treating RTK resistant cancer (see Example 1 of the instant application).
In addition, other than binding to antigen avb3, the claims identify the antibodies by other functions, where the function is:
treating RTK-resistant cancer in combination with an RTK inhibitor, wherein the RTK comprises erlotinib, such as erlotinib (claim 4);
initiating ADCC killing of the avb3-expressing epithelial cancer (claim 7).
treating subject with decreased ratio of M1 to M2 macrophages (claim 12).
The specification and prior art have not established the relationship between the claimed functions and the structure of the antibody. One of ordinary skill in the art would not be able to readily recognize/visualize an antibody with the required functions. Taken together, applicant has not provided sufficient evidence to show that the inventors possess a genus of anti-avb3 antibodies as claimed.
Although Applicants may argue that it is possible to screen for antibodies that bind and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. "As we held in Lilly, "[a]n adequate written description of a DNA ... 'requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention." 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171 ). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions." Knowledge of screening methods provides no information about the structure of any future antibodies or engineered Fc domains yet to be discovered that may function as claimed.
Taken together, the instant specification has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between functions and the structure of the antibody by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of antibodies broadly encompassed to treat an RTK-resistant epithelial cancers by the claimed invention.
Response to Arguments
For the rejection under 35 U.S.C. 112(a), Applicant argues:
Amended independent claim 1 now recites wherein the anti-avb3 integrin antibody comprises a means for binding to a human avb3 polypeptide.
Applicant's specification provides numerous examples by way of specific sequences and known antibodies that bind to avb3. Specifically, paragraph [0022] provides specific examples of antibodies having binding fragments capable of binding to a human avb3 polypeptide, for example LM609, monoclonal antibody CBL544, monoclonal antibody ab7166, and monoclonal antibody ab78289. These antibodies were all known antibodies to possess specific binding to avb3 such that one of skill in the art would readily understand that the specification provides written support for a genus of antibodies having a means for binding to human avb3.
Applicant’s arguments have been fully considered but they are only partially persuasive. In view of claim amendments and applicant’s arguments, the rejection for amended claim 3 is hereby withdrawn. However, for other rejected claims, as discussed above in this office action under 35 USC 112(f), the recited “means for binding” is structurally modified by the requirement that it be an antibody. This means that the term is NOT being interpreted to cover only the corresponding structure, material, or acts described in the specification as performing the claimed function, and equivalents thereof (e.g. the specific antibodies of paragraph [0022]. Given BRI, the antibodies can be monoclonal antibodies or polyclonal antibodies (known or yet to be discovered) with different origins (including human antibodies, as evidenced by claim 11); the antibodies can bind to different epitope of avb3. One of ordinary skill in the art would not be able to readily recognize/visualize the anti-avb3 antibodies which would have had the same properties and functionalities as the anti-avb3 antibody: LM609, which has properties required for claimed methods.
Applicant further argues:
Furthermore, "[a]n applicant need not disclose a nucleotide or amino acid sequence of claimed antibodies in order to satisfy the written description requirement if such sequences are already known in the prior art." See Juno Therapeutics, Inc. v. Kite Pharma, Inc., IO F.4th 1330, 1337 (Fed. Cir. 2021) (discussing scFv antibody fragments). In Applicant's specification, there is ample support for antibody sequences known to bind to avb3 as well as existing antibodies that have avb3-specific binding. Accordingly, the skilled artisan would recognize that Applicant was in possession of antibodies and therefore the claims, comprising a means for binding avb3 as presently claimed.
Applicant’s arguments have been fully considered but they are not persuasive. Regarding the argument “an applicant need not disclose a nucleotide or amino acid sequence of claimed antibodies in order to satisfy the written description requirement if such sequence are already known in the prior art”, in the instant case, the claims encompass a broad genus of anti-avb3 antibodies known or yet to be discovered. Thus, the claims encompass antibodies with unknown sequences. As set forth above, by the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope. The sequences of a known antibody would not tell the sequence of other antibodies which bind to the same antigen. In addition, the claims identify the antibodies by other functions, including:
treating RTK-resistant cancer in combination with an RTK inhibitor, wherein the RTK comprises erlotinib, such as erlotinib (claim 4);
initiating ADCC killing of the avb3-expressing epithelial cancer (claim 7).
treating subject with decreased ratio of M1 to M2 macrophages (claim 12).
The specification and prior art have not established the relationship between the claimed functions and the structure of the antibody. One of ordinary skilled in the art would not be able to readily recognize/visualize an antibody with required functions. Taken together, applicant has not provided sufficient evidence to show that the inventors possess a genus of anti-avb3 antibodies as claimed.
Therefore, the rejection is maintained for the reasons of record.
NEW OBJECTIONS AND REJECTIONS
Claim Objections
Claim 5 is objected to because of the following informalities: “the expression of avb3 expression” should be “the expression of avb3”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 5 and 8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites the limitation "the human anti-avb3 integrin antibody" in line 2. There is insufficient antecedent basis for this limitation in the claim because claim 1 recites “a human anti-avb3 integrin polypeptide”.
Claims 5 and 8 are also rejected because these claims depend on claim 2.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 5, 8 and 9 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. This is a NEW MATTER rejection.
Claim 5 was amended after the filing date. The limitation of “the method of claim 2, further comprising detecting the expression of avb3 expression in a sample isolated from the subject following administration of the RTK inhibitor” in claim 5 has no clear support in the specification as originally filed. Applicant argues in the Remarks of 09/25/2025 that support for the limitation can be found in the specification as filed, for example, in paragraphs [0022], [0024], [0026], and [0112]. The paragraphs are shown below:
[0022] In alternative embodiments, provided are methods: wherein the antibody or polypeptide is a humanized antibody, optionally a humanized murine antibody; or wherein the antibody or polypeptide is a recombinant or engineered antibody; or wherein the antibody is a human antibody; or, wherein the antibody is monoclonal antibody, or a polyclonal antibody; or wherein the antibody is: monoclonal antibody LM609 (Chemicon Int., Temecula, CA) (CVCL_KS89) (the murine hybridoma having ATCC accession number HB 9537) (see e.g., U.S. Pat. No. 7,115,261); monoclonal antibody CBL544, derived from clone 23C6 (MilliporeSigma, Burlington, MA); monoclonal antibody ab7166 (abcam, Cambridge, MA); or, monoclonal antibody ab78289 (abcam, Cambridge, MA); or, or any humanized version thereof, or any polypeptide comprising an αvβ3-binding CDR of LM609, CBL544, ab7166 or ab78289.
Paragraph [0022] gives general description of antibody and a few available avb3 antibodies.
[0024] In alternative embodiments, provided are methods: wherein the cancer is an epithelial cancer or epithelial tumor cell; or wherein the cancer is a drug resistant cancer, and optionally the drug is a growth factor inhibitor or a kinase inhibitor, wherein optionally the growth factor inhibitor comprises a Receptor Tyrosine Kinase (RTK) inhibitor, optionally erlotinib.
Paragraph [0024] discloses treating RTK inhibitor resistant epithelial cancers with a RTK inhibitor, e.g. erlotinib.
[0026] In alternative embodiments, provided are methods further comprising administration of a growth factor inhibitor, wherein optionally the growth factor inhibitor comprises a Receptor Tyrosine Kinase (RTK) inhibitor, a Src inhibitor, an anti-metabolite inhibitor, a gemcitabine, a GEMZAR™, a mitotic poison, a paclitaxel, a taxol, an ABRAXANE™, an erlotinib, a TARCEVA™, a lapatinib, a TYKERB™, a cetuxamib, an ERBITUX™, or an insulin growth factor inhibitor.
Paragraph [0026] discloses the methods further comprising administering RTK inhibitors.
[0112] Alternative embodiments can use “humanized” antibodies, including forms of non-human (e.g., murine) antibodies that are chimeric antibodies comprising minimal sequence (e.g., the antigen binding fragment) derived from non-human immunoglobulin. In alternative embodiments, humanized antibodies are human immunoglobulins in which residues from a hypervariable region (HVR) of a recipient (e.g., a human antibody sequence) are replaced by residues from a hypervariable region (HVR) of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In alternative embodiments, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues to improve antigen binding affinity.
Paragraph [0112] give general description of humanized antibodies.
Besides the paragraphs listed above, Fig. 4B and paragraph [0066] show cells from erlotinib resistant tissue were αvb3-positive while the cells from the vehicle treated animal were not, in PC9 xenograft model.
Taken together, the claims and specification as originally filed provide support for only specific RTK inhibitor: erlotinib leads to avb3 expression which is associated with erlotinib resistant for one specific cancer. Thus, the claims and specification as originally filed do not support “the method of claim 2, further comprising detecting the expression of avb3 expression in a sample isolated from the subject following administration of the RTK inhibitor”, which encompassed a broad genus of RTK inhibitor and a broad genus of RTK inhibitor-resistant epithelial cell cancers.
Claim 8 was amended after the filing date. The limitation of “the method of claim 2, further comprising detecting the concentration of tumor associated macrophages in the subject following administration of the RTK inhibitor” in claim 8 has no clear support in the specification as originally filed. Applicant argues in the Remarks of 09/25/2025 that support for the limitation can be found in the specification as filed, for example, in paragraphs [0022], [0024], [0026], and [0112]. As shown above, paragraphs [0022], [0024], [0026], and [0112] does not support the amended claim 8.
Fig. 1l and paragraph [0127] show a higher number of TAMs, particularly of M2 type TAM in erlotinib-treated lung adenocarcinoma patient tumors.
Taken together, the claims and specification as originally filed provide support for only specific RTK inhibitor: erlotinib leads to an increased M2 type TAM in a specific erlotinib-resistant lung adenocarcinoma. Thus, the claims and specification as originally filed do not support “the method of claim 2, further comprising detecting the expression of avb3 expression in a sample isolated from the subject following administration of the RTK inhibitor”, which encompassed a broad genus of RTK inhibitor and a broad genus of RTK inhibitor-resistant epithelial cell cancers.
Similarly, claim 9 was amended after the filing date. The limitation of “wherein administration of the RTK inhibitor increases the concentration of tumor associated macrophages (TAM)” in claim 9 has no clear support in the specification as originally filed. As set forth above, the claims and specification as originally filed provide support for only specific RTK inhibitor: erlotinib leads to an increased M2 type TAM in a specific erlotinib-resistant lung adenocarcinoma patients. Thus, the claims and specification as originally filed do not support “wherein administration of the RTK inhibitor increases the concentration of tumor associated macrophages (TAM)”, which encompassed a broad genus of RTK inhibitor and a broad genus of RTK inhibitor-resistant epithelial cell cancers.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7, 9-11, 13 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Cheresh (Cheresh et al. WO 2012/167028 A2, Publication Date: 06-12-2012, cited in IDS, of record), as evidenced by the instant publication US 2024/0067733 A1.
Cheresh teaches a treatment comprising blocking activation of an αvb3, or blocking the interaction of a ligand with an αvb3, with small molecule, peptide, polypeptide or antibody (Abstract, claims 1 and 3).
Cheresh teaches that avb3 polypeptide is found on tumor but not normal vessels (Fig. 9A-B) and is required for angiogenesis and tumor growth (Fig. 10). In some tumors (including breast, cervical and pancreatic cancers which are all epithelial cancers), expression of avb3, correlates with tumor progression and metastasis (Fig. 11). Thus, these tumors read on avb3 polypeptide expressing epithelial cell cancers.
Cheresh teaches that αvb3 expression in epithelial cell cancer promotes resistance to EGFR TKI; e.g. erlotinib (pancreatic and colon cancer cells) or lapatinib (breast cancer cells) (Fig. 26A-G, Table 1). As evidenced by instant claim 4, erlotinib reads on the RTK inhibitor of claims 1 and 4. And pancreatic cancer and breast cancer are epithelial cell cancers.
Cheresh teaches that αvb3 was required and sufficient to induce erlotinib resistance since: 1) knockdown of avb3 in PANC- cells resulted in 10-fold increase in tumor cell sensitivity to erlotinib; 2) ectopic expression of αvb3 in FG cells lacking this integrin dramatically increased erlotinib resistance both, in vitro and in orthotopic pancreatic tumors (Figs. 26f and g, page 62, para. 1).
Cheresh teaches that a tumor or a cancer with an increased level or amount of αvb3 integrin in or on the cell as compared to normal, normalized or wild type cells indicates that the individual or patient would be benefit from a therapy comprising administering an inhibitor that depletes avb3, such as LM609 (page 13-14, claim 20).
Note that LM609 is the only antibody used in the Examples of the instant specification. As evidenced by the instant publication US 2024/0067733 A1, antibody LM609 has the properties: a) bind a human avb3 integrin polypeptide expressed on the RTK inhibitor-resistant polypeptide-expressing epithelial cell cancer (Fig. 2B); b) capable of binding a macrophage and initiating ADCC killing of the avb3 polypeptide-expressing epithelia cell cancer ([0121], [0129], Figs. 3A and 3B); has a Fc comprising a means for binding to a human macrophage (Fig. 3C). Thus, LM609 would read on the antibody of the instant claims 1, 3, 7 and 13.
Cheresh teaches use of a combination of compounds for overcoming or diminishing or preventing Growth Factor Inhibitor (GFI) resistance in a cell, or a method for re-sensitizing a cell to a GFI, wherein the combination compounds comprises: (i) an inhibitor or depleter of integrin avb3, or an inhibitor of integrin avb3 protein activity; and (ii) a Growth Factor Inhibitor, wherein the cell is a tumor cell, a cancer cell (page 14-line 21 to page 15-line 16). Cheresh teaches that erlotinib is an exemplary GFI (page 12 lines 17-20). Cheresh teaches that antibody LM609 is an exemplary avb3 inhibitor (page 12, lines 10-14).
Cheresh teaches as set forth above. Cheresh does not explicitly teach administering an RTK inhibitor and an anti-avb3 integrin antibody for treating a RTK inhibitor-resistant avb3 polypeptide-expressing epithelial cell cancer in a subject in need of as instantly claimed. However, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use a combination of RTK inhibitor (e.g. erlotinib) and an anti-avb3 antibody (e.g. LM609) because Cheresh teaches that 1) the combination can overcome Growth Factor Inhibitor (GFI) resistance in a cancer cell; 2) αvb3 expression in epithelial cell cancer promotes resistance to EGFR TKI; e.g. erlotinib (pancreatic and colon cancer cells) (Fig. 26A-G, Table 1); 3) αvb3 was required and sufficient to induce erlotinib resistance since: i) knockdown of avb3 in PANC- cells resulted in 10-fold increase in tumor cell sensitivity to erlotinib; ii) ectopic expression of αvb3 in FG cells lacking this integrin dramatically increased erlotinib resistance both, in vitro and in orthotopic pancreatic tumors (Figs. 26f and g, page 62, para. 1); 4) antibody LM609 is an exemplary avb3 inhibitor (page 12, lines 10-14). Based on the teachings of Cheresh, one of ordinary skill in the art would have expected that combination of an RTK inhibitor: erlotinib and an anti-avb3 antibody: LM609 would be effective to overcome erlotinib resistance in epithelial cell cancer (e.g. pancreatic cancers), because increased avb3 expression is associated with erlotinib-resistance and LM609 can inhibit avb3 activity. The motivation would have been to develop a combination therapy for a suitable patient population.
Regarding claim 2 and 6, there are only three options to administer the RTK inhibitor and antibody: 1) RTK inhibitor is administered following administration of the antibody; 2) RTK inhibitor is administered before administration of the antibody; 3) RTK inhibitor is administered at the same time as administration of the antibody. One of ordinary skill in the art would have known to test different administration regimen to achieve the best therapeutic outcomes through routine experimentation, absent a showing of criticality or unexpected results.
Regarding claim 5, as the data shown in Fig. 26 and Table 1 of Cheresh, avb3 expression is the best predictor about the sensitivity of an epithelial cell cancer (e.g. pancreatic cancer, lung cancer, and breast cancer) to erlotinib treatment. Cheresh also teaches detecting the levels or amount of avb3 in a sample and from the patient and wherein a finding of increased levels of avb3 indicates that the individual or patient would be benefit from the combination therapy (see page 13, lines 15-30). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat an epithelial cell cancer with erlotinib and then identify patients who has increased expression of avb3 by detecting avb3 expression in a sample isolated from the patient, and then treat the patients with anti-avb3 antibody: LM609 because these patients are more likely to be benefit from the combination therapy targeting avb3 as taught by Cheresh.
Regarding claim 7, as evidenced by the instant publication, LM609 is capable of binding a macrophage and initiating ADCC killing of the avb3 polypeptide-expressing epithelia cell cancer ([0121], [0129], Figs. 3A and 3B of the instant publication US 2024/0067733 A1).
Regarding claim 9, as evidenced by the instant publication, erlotinib increase M2 TAM concentration (Fig. 1l of the instant publication US 2024/0067733 A1). Cheresh teaches administration of the same RTK inhibitor: erlotinib, thus, the administration step would lead to the same outcome: increase the concentration of M2 TAM.
Regarding claim 10, LM609 is a humanized murine antibody, as evidenced by [0022] of the instant publication US 2024/0067733 A1.
Regarding claims 11, 13 and 14, Cheresh teaches that completely human antibodies also can be used to practice this invention, including human antibodies comprising amino acid sequence which corresponds to that of an antibody produced by a human (page 56, lines 24-28). A full length human antibodies would comprise a Fc domain of a human immunoglobulin which can bind Fc receptors on the surface of human macrophage.
In addition, regarding claim 13, LM609 has a Fc comprising a means for binding to a human macrophage, as evidenced by Fig. 3C of the instant publication US 2024/0067733 A1.
Claims 8 and12 are rejected under 35 U.S.C. 103 as being unpatentable over Cheresh (Cheresh et al. WO 2012/167028 A2, Publication Date: 06-12-2012, of record), as evidenced by the instant publication US 2024/0067733 A1, as applied to claims 1-7, 9-11, 13 and 14 above, and further in view of Zhang (Zhang et al., Med Oncol, (2014) 31: 127, Publication Date: 07/18/2014, of record).
Cheresh teaches the method of claims 1 and 2, as set forth above. However, Cheresh does not teach detecting the concentration of tumor associated macrophages in the subject following administration of the RTK inhibitor, or the subject in need thereof expresses a decreased ratio of M1 to M2 macrophages as compared to a healthy subject.
Zhang teaches that previous study has revealed that tumor-associated macrophages (TAMs) correlate with response to epidermal growth factor receptor-tyrosine kinase (RTK) inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) (Abstract).
Zhang teaches that the EGFR-TKIs are erlotinib or gefitinib which shows dramatic antitumor activity against NSCLC (page 1, col. 2, para. 2; and page 4, col. 1, para. 2). Note that NSCLC is a type of epithelial cell cancer that begins in the epithelial cells lining the lungs.
Zhang teaches that M1 macrophages are activated macrophages and are potent effector cells that kill tumor cells; M2 macrophages play an important role in tumor growth, angiogenesis and immunosuppression (the bridging paragraph of pages 5-7).
Zhang teaches that patients with higher count of M2-macrophages (independent of EGFR status) are less responsive to EGFR-TKIs (Fig. 2 and § Treatment response and M1- or M2- polarized TAMs). The EGFR-TKIs used in the study are gefitinib and erlotinib (see page 127, col. 1, para. 2).
Zhang teaches the methods of detecting tumor associated macrophages (M1 and M2 TAM) (the bridging paragraph of pages 2-3).
Regarding claim 8, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat an epithelial cell cancer with erlotinib and then identify patients who has increased concentration of M2 TAM by measuring M2 TAM in a sample isolated from the patient, and then add the anti-avb3 antibody (e.g. LM609) in the treatment: because Zhang teaches that an increased in M2 macrophage counts an is independent predictor for resistance to EGFR-TKIs (e.g. erlotinib) therapy, thus one of ordinary skilled in the art would have expected that the avb3 antibodies such as LM609 would help to overcome TKI resistance in the subjects with increased M2 TAM. The motivation would have been to develop a treatment for this population and identify a population suitable for the claimed treatment.
Regarding claim 12, based on teachings of Cheresh and Zhang, it would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use an anti-avb3 antibody such as LM609 in combination with RTK inhibitor such as erlotinib to treat an EGFR-TKIs resistant cancer in a subject with higher M2-macrophages which would have a decreased ratio of M1 to M2 macrophages as compared to a healthy subject. Because Cheresh teaches avb3 is necessary and sufficient to induce a3Vb EGFR-TKIs resistance, antibody LM609 can overcome resistance to EGFR-TKIs, and Zhang teaches that an increased in M2 macrophage counts is independent predictor for resistance to EGFR-TKIs (e.g. erlotinib) therapy, thus one of ordinary skilled in the art would have expected that the avb3 antibodies such as LM609 would help to overcome TKI resistance in the subjects with a decreased ration of M1 to M2 macrophages. The motivation would have been to develop a treatment for this population and identify a population suitable for the claimed treatment.
Response to Arguments
For the rejection under 35 U.S.C. 103, Applicant argues:
Applicant surprisingly discovered that administration of growth factor inhibitors, such as receptor tyrosine kinase inhibitors, administered to patients suffering from epithelial cell cancer results the development of cancer cell drug resistance and the enrichment of avb3 expression on the epithelial cell cancer cells. Applicant's Specification, at paragraph [0072] and FIGS. 4B and 6. Moreover, the enrichment of avb3 expression leads to the accumulation of M2 tumor associated macrophages resulting in the cancer's manipulation of the subject's immune system to support cancer proliferation and metastasis. Id at paragraph [0172]. Thus, while erlotinib can initially limit tumor growth, this therapy ultimately creates a more aggressive tumor by enriching for avb3/ALDH1Al-expressing cells and recruiting tumor-associated macrophages. Id Applicant discovered that patients that develop drug-resistant cancers following the administration of an RTK inhibitor represent a patient population that are especially suited for the treatment with avb3-targeting cancer therapies due to the increased expression of avb3 and macrophage enrichment in the tumor environment. Id at [0124]
Applicant’s arguments have been fully considered but they are not persuasive.
First, Cheresh explicitly teaches that αvb3 expression in epithelial cell cancer promotes resistance to EGFR TKI; e.g. erlotinib (pancreatic and colon cancer cells) or lapatinib (breast cancer cells) (Fig. 26A-G, Table 1). In addition, αvb3 was required and sufficient to induce erlotinib resistance since: 1) knockdown of avb3 in PANC- cells resulted in 10-fold increase in tumor cell sensitivity to erlotinib; 2) ectopic expression of αvb3 in FG cells lacking this integrin dramatically increased erlotinib resistance both, in vitro and in orthotopic pancreatic tumors (Figs. 26f and g, page 62, para. 1); 3) avb3 inhibitor such as LM609 can help to overcome resistance and re-sensitize the cancer cells (page 14-line 21 to page 15-line 16). Thus, the administration of RTK inhibitors such as erlotinib results the erlotinib resistance and avb3 expression is closely associated with erlotinib resistance; and avb3 inhibitor would overcome resistance or resensitize cancer cells to erlotinib. Based on the teachings of Cheresh, even without knowing that erlotinib administration increase avb3 expression, one of ordinary skill in the art would have used an avb3 targeting therapy comprising antibody LM609 for treating erlotinib resistant cancers.
Second, applicant alleges that the enrichment of avb3 expression leads to the accumulation of M2 TAM. However,