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, paragraph [0127] of the specification only teaches that erlotinib resistant lung adenocarcinoma tumor has higher M2 type TAM. Also as shown in Fig. 1l, it’s erlotinib (not avb3) leads to the accumulation of M2 type TAM. As set forth above, Cheresh teaches using a combination of erlotinib an LM609 to treat erlotinib resistant epithelial cancers. Zhang teaches M2 type TAM is an independent predictor for erlotinib resistance. Thus, the teachings of Cheresh would lead to the claimed method because LM609 (an exemplary avb3 inhibitor) would be effective to overcome erlotinib resistance in epithelial cell cancer (e.g. pancreatic cancers), and increased avb3 expression is associated with erlotinib-resistance. Combined with teachings of Zhang, one of ordinary skill in the art would have recognized that the erlotinib-treated patients with high amount of M2 type TAM are more likely to be erlotinib resistant and are suitable for the combination treatment.
Regarding RTK inhibitor resistant cancer patients that are suitable patient population for avb3-targeting cancer therapies due to the increased expression of avb3 and macrophage enrichment in the tumor environment, Cheresh explicitly teaches: 1) αvb3 expression in epithelial cell cancer promotes resistance to EGFR TKI; e.g. erlotinib (pancreatic and colon cancer cells) (Fig. 26A-G, Table 1); 2) αvb3 was required and sufficient to induce erlotinib resistance (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 to RTK inhibitor (page 14-line 21 to page 15-line 16). Thus, even without knowing erlotinib leads to the accumulation of M2 type TAM, one of ordinary skill in the art would have recognize that the erlotinib-resistant cancers are suitable for avb3-targeting cancer therapies.
Applicant further argues:
Applicant also discovered that administering avb3-specific antibodies in combination with an RTK inhibitor not only maintained drug sensitivity by targeting the emerging avb3 cancer stem cells that are enriched through RTK inhibitor administration, but that the avb3-antibody therapy was able to utilize the accumulated macrophages - which ordinarily would promote cancer progression - to initiate macrophage assisted antibody-dependent cell cytotoxicity (ADCC). Id at Example 1. The surprising nature of this discovery is twofold. First, it was not known that RTK inhibitor-resistance was correlated with avb3 expression. Second, the ability to utilize the enriched macrophage environment against the cancer cells runs contrary to the expectation that antibodies generally initiated ADCC through their interactions with nature killer cells. Id at paragraph [0129]
Applicant’s arguments have been fully considered but they are not persuasive.
Regarding surprising nature of the results, Cheresh explicitly teaches that αvb3 expression in epithelial cell cancer promotes resistance to EGFR TKI; e.g. erlotinib (pancreatic and colon 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). One of ordinary skill in the art would have expected the LM609 would overcome erlotinib-resistance of cancer cells. Thus, the effectiveness of the combination of erlotinib and LM609 is not unexpected.
Regarding that the anti-avb3 antibody therapy was able to utilize the accumulated macrophages to initiate macrophage assisted antibody-dependent cell cytotoxicity (ADCC), the claims do not recite the limitations thus the references do not need to teach/suggest this. Furthermore, the specification only shows that M2 TAM is increased in erlotinib treated lung cancer cells ([0127] and Fig. 1l of the instant publication US 2024/0067733). As evidenced by paragraph [0128] of the instant publication US 2024/0067733, LM609 has been known to initiate ADCC. Thus, LM609 is capable of initiating ADCC is not surprising. In addition, even without knowing the alleged effects of TAM, based on teachings of Cheresh, one of ordinary skill in the art would have reached the claimed method, because the combination would overcome erlotinib-resistance of cancer cells, as suggested by Cheresh. In addition, Cheresh teaches administration the same antibody LM609 and the same combination as the instant application, thus, the antibody and combination taught by Cheresh would have the same therapeutic properties as the antibody and combination tested in the instant specification.
Additionally, the therapeutic results of the specification are based on one specific combination: erlotinib and LM609 for one specific cancer model. The claims are not limited to this combination and encompass a broad genus of RTK inhibitors, a broad genus of anti-avb3 antibodies and a broad genus of epithelial cancers. Thus, the example is not commensurate in scope with the claimed invention and is not probative on the non-obviousness of the claimed invention.
Applicant further argues:
Accordingly, the present claims are directed to a specific population that is especially susceptible to dual treatment with an RTK inhibitor and an avb3-specific antibody, particularly following the confirmation of drug resistance through the detection of increased avb3 expression or the enrichment of tumor associated macrophages.
The combination of Cheresh, Wu, and Zhang fails to teach or suggest the claimed method. Specifically, neither Cheresh, Wu, nor Zhang teach that RTK inhibitor administration results in drug resistance identified by the accumulation of tumor-associated macrophages and the enrichment of avb3 expression in epithelial cancer cells. Moreover, none of the cited references teach or suggest that administration of an RTK inhibitor in combination with an avb3-targeting antibody utilizes the mechanism leading to drug resistance to turn the body's immune system against the cancer by targeting both the increased expression of avb3 and the accumulation of macrophages in the tumor environment to initiate macrophage assisted ADCC against cancer stem cells that ordinarily would promote metastasis and tumor progression.
Applicant’s arguments have been fully considered but they are not persuasive.
Although Cheresh, nor Zhang teach that RTK inhibitor administration results in drug resistance identified by the accumulation of TAM and the enrichment of avb3 expression, Cheresh and Zhang clearly teaches that erlotinib-resistance is closely associated with the expression of avb3 and the accumulation of M2 type TAM. Cheresh teaches cancers with increased avb3 expression would benefit from avb3 targeting therapy. Cheresh teaches that LM609 can overcome resistance and resensitize cancer cells (including epithelial cancers) to erlotinib treatment. Thus, based on the teachings of Cheresh and Zhang, one of ordinary skill in the art would have recognized that the combination of erlotinib and LM609 would be effective to treat the patient population with erlotinib-resistant avb3 polypeptide-expressing epithelial cell cancers.
Regarding the argument that none of the cited references teach or suggest that the claimed combination utilizes the mechanism leading to drug resistance to turn the body’s immune system against the cancer by targeting both the increased expression of avb3 and the accumulation of TAM to initiate macrophage assisted ADCC, the claims do not recite the limitations. Thus, the references do not need to teach/suggest all the recited mechanism of actions for the combination treatment.
Additionally, the therapeutic results of the specification are based on one specific combination: erlotinib and LM609 for one specific epithelial cancer (lung cancer). The claims are not limited to this combination and encompass a broad genus of RTK inhibitors, a broad genus of anti-avb3 antibodies and a broad genus of epithelial cancers. Thus, the example is not commensurate in scope with the claimed invention and is not probative on the non-obviousness of the claimed invention.
Applicant further argues:
Rather, Cheresh allegedly teaches a treatment comprising blocking activation of an avb3, or blocking the interaction of a ligand with an avb3, with small molecule, peptide, polypeptide or antibody. Wu allegedly teaches that the inhibition of the vitronectin-binding av~3 integrin also inhibits the process of tumor angiogenesis. Zhang allegedly teaches that previous study has revealed that tumor-associated macrophages (TAMs) correlate with response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer. However, none of the cited references, alone or in combination, teach or suggest treating an RTK resistant avb3-expressing epithelial cell cancer in a subject in need thereof with an RTK inhibitor in combination with an avb3-targeting antibody with any reasonable expectation of success. In fact, one of skill in the art would have been motivated to avoid administration of an RTK inhibitor to a cancer resistant to said drug.
Regarding applicant’s argument that one of ordinary skill in the art would not have reasonable expectation of success for the claimed method, Applicant’s arguments have been fully considered but they are not persuasive.
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 (an exemplary avb3 inhibitor) 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.
Furthermore, in the field of biological technology, no invention has absolute certainty of success before experimental tests. Thus, only a reasonable expectation of success (not absolute) would have motivated an artisan to develop the claimed method. Given the teachings from references, an ordinary skilled in the art would have would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the rejection is maintained for the reasons of record.
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.
U.S. Patent No. 6,887,473
Claims 1-7, 9-11, 13 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-63 of U.S. Patent No. 6,887,473 (thereinafter Pat. 473, of record), in view of 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.
The claims of Pat. 473 teach a method of inducing tumor tissue regression in a patient comprising administering to said patient a therapeutically effective amount of an antibody immunospecific for αvβ3, such as a humanized monoclonal antibody (claims 1 and 51).
The claims of Pat. 473 teach that the antibody is a monoclonal antibody (claim 2)
The claims of Pat. 473 teach that the solid tumor is bladder tumor, breast tumor, colon tumor, lung tumor, skin tumor, carcinoma, or melanoma (claims 3-10, 53-59). Carcinoma reads on epithelial cancer.
The claims of Pat. 473 teach that the administration can be conducted in conjunction with chemotherapy (claim 26).
The claims of Pat. 473 teach that the patient is human (claim 27).
The claims of Pat. 473 teach that antibody specifically binds integrin αvβ3 complex (claim 33).
The claims of Pat. 473 teach that monoclonal antibody or the humanized monoclonal antibody has the immunoreaction characteristics of monoclonal antibody LM609 having ATCC accession number HB9537 (claims 39 and 52)
The claims of Pat. 473 teach that the antibody is a humanized monoclonal antibody (claim 40).
The claims of Pat. 473 teach the antibody is administered in a composition. And the composition is a sterile pharmaceutical composition (claims 42-43).
The claims of Pat. 473 teach the antibody preferentially binds αvβ3 over other integrins (claim 60).
Taken together, the claims of Pat. 473 teach treating tumor with an avb3 antibody, such as LM609 or humanized antibodies. However, the claims do not teach the cancer is a RTK inhibitor resistant avb3 polypeptide-expressing epithelial cancer, the antibody binds to human macrophages, the method comprises administering a RTK inhibitor such as erlotinib, the antibody can initiate ADCC killing of the avb3 polypeptide expressing epithelial cancer, or wherein the antibody is a human antibody, or the Fc domain is derived from a human immunoglobulin.
Cheresh teachings are set forth above. In particular, Cheresh teaches 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 of 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 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 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).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat a tumor with an avb3 antibody such as LM609 or humanized LM609 as taught by the claims of Pat. 473, and to expand the treatment to a Growth Factor Inhibitor (GFI) resistant (e.g. erlotinib resistant) avb3 expressing epithelial cell cancers by administering a combination of erlotinib and humanized LM609 and because Cheresh teaches that avb3 is required and sufficient to induce erlotinib resistance in cancers and avb3 antibody can be used to overcome GFI resistance and resensitize cancer cells to GFI (e.g. erlotinib). Based on the teachings of the claims of Pat. 473, Cheresh, one of ordinary skilled in the art would have expected that LM609 and erlotinib combination would be effective to treat erlotinib-resistant avb3 expressing epithelial cell cancer in the method taught by Cheresh. The motivation would be to develop a more effective method for a erlotinib resistant epithelial cell cancer. Given that the composition and administration are well known in the art, one of ordinary skill in the art would have a reasonable expectation of success to reach the claimed method because LM609 would help to overcome erlotinib resistance and resensitize the cancer cells to erlotinib.
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 modify the method of Pat. 473 and 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 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).
Regarding claim 9, as evidenced by the instant publication, erlotinib increase M2 TAM concentration (Fig. 1l of the instant publication US 2024/0067733 A1). Because the claims of Pat. 473 and Cheresh teaches administration of the same RTK inhibitor: erlotinib, the administration step would lead to the same outcome: increase the concentration of 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. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method of Pat. 473 by replacing a LM609 with a human anti-avb3 antibody for treating a human subject in order to improve the therapeutic properties for treating human.
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 and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-63 of U.S. Patent No. 6,887,473 (thereinafter Pat. 473, of record), in view of 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, 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).
The claims of Pat. 473 and Cheresh teach the methods of claim 1 and claim 2 as set forth above. However, the claims of Pat. 473 and Cheresh do 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-macrpphages (independent of EGFR status) are less responsive to EGFR-TKIs (Fig. 2 and § Treatment response and M1- or M2- polarized TAMs).
Zhang teaches the methods of detecting tumor associated macrophages (M1 and M2 TAM) (the bridging paragraph of pages 2-3).
Regarding claims 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 LM609 as taught by the claims of Pat. 473 and Cheresh, and to modify the method by identifying patients who has increased concentration of M2 TAM by measuring M2 TAM in a sample isolated from the patient after erlotinib treatment, and then add the anti-avb3 antibody (e.g. LM609) in the treatment for patients with increased concentration of M2 TAM: because 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 erlotinib 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 the claims of Pat. 473, 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.
U.S. Patent No. 7,482,007
Claims 1-7, 9-11, 13 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 7,482,007 (thereinafter Pat. 007, of record), in view of 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.
The claims of Pat. 007 teach a method of inhibiting angiogenesis to treat cancer in a patient comprising administering to said patient a therapeutically effective amount of an antibody immunospecific for αvβ3, wherein said antibody inhibit tumor angiogenesis (claim 1).
The claims of Pat. 007 teach that the cancer can be melanoma, colon cancer, breast cancer, bladder cancer, lung cancer, metastatic melanoma (claims 2-7). Note that colon cancer, breast cancer, bladder cancer, and lung cancer are epithelial cell cancers.
The claims of Pat. 007 teach that the antibody is a monoclonal antibody or an antibody fragment (claims 8 and 11).
The claims of Pat. 007 teach that the antibody is a humanized antibody or an antibody fragment (claims 9 and 12).
The claims of Pat. 007 teach intravenous administration (claim 13).
The claims of Pat. 007 teach that the administration can be conducted in conjunction with chemotherapy (claim 17).
The claims of Pat. 007 teach that antibody specifically binds integrin αvβ3 complex (claims 18-20).
The claims of Pat. 007 teach the antibody preferentially binds αvβ3 over other integrins (claims 21-26).
Taken together, the claims of Pat. 007 teach treating tumor with an avb3 antibody, or humanized avb3 antibodies. However, the claims do not teach the cancer is a RTK resistant avb3 polypeptide-expressing epithelial cell cancer, further comprising administering a RTK inhibitor such as erlotinib, the antibody can initiate ADCC killing of the avb3 polypeptide expressing cancer, or wherein the antibody is a human antibody, or specific antibody such as LM609, or steps of detecting avb3 expression level, or specific administration steps.
Cheresh teachings are set forth above. In particular, Cheresh teaches use of a combination of compounds for overcoming or diminishing or preventing RTK inhibitor resistance in a cell, or a method for re-sensitizing a cell to a GFI, wherein the combination compounds comprises: (i) an inhibitor of 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 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 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).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat a epithelial cell cancer with an avb3 antibody or humanized avb3 antibody as taught by the claims of Pat. 007, and to expand the treatment to a RTK resistant (e.g. erlotinib resistant) avb3 expressing epithelial cell cancers by administering a combination of erlotinib and humanized LM609 and because Cheresh teaches that avb3 is required and sufficient to induce erlotinib resistance in cancers and avb3 antibody can be used to overcome RTK inhibitor resistance and resensitize cancer cells to RTK inhibitor (e.g. erlotinib), LM609 is an exemplary avb3 inhibitor. Based on the teachings of the claims of Pat. 007 and Cheresh, one of ordinary skilled in the art would have expected that LM609 and erlotinib combination would be effective to treat erlotinib-resistant avb3 expressing epithelial cell cancer in the method taught by Cheresh. The motivation would be to develop a more effective method for an erlotinib resistant epithelial cell cancer. Given that the composition and administration are well known in the art, one of ordinary skill in the art would have a reasonable expectation of success to reach the claimed method because LM609 would help to overcome erlotinib resistance and resensitize the cancer cells to erlotinib.
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 modify the method of Pat. 007 and 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 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).
Regarding claim 9, as evidenced by the instant publication, erlotinib increase M2 TAM concentration (Fig. 1l of the instant publication US 2024/0067733 A1). Because the claims of Pat 007 and Cheresh teaches administration of the same RTK inhibitor: erlotinib, the administration step would lead to the same outcome: increase the concentration of 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. It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method of Pat. 007 by replacing a LM609 with a human anti-avb3 antibody for treating a human subject in order to improve the therapeutic properties for treating human.
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 and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 7,482,007 (thereinafter Pat. 007, of record), in view of 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, 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).
The claims of Pat. 007 and Cheresh teach the methods of claim 1 and claim 2 as set forth above. However, the claims of Pat. 473 and Cheresh do 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-macrpphages (independent of EGFR status) are less responsive to EGFR-TKIs (Fig. 2 and § Treatment response and M1- or M2- polarized TAMs).
Zhang teaches the methods of detecting tumor associated macrophages (M1 and M2 TAM) (the bridging paragraph of pages 2-3).
Regarding claims 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 LM609 as taught by the claims of Pat. 007and Cheresh, and to modify the method by identifying patients who has increased concentration of M2 TAM by measuring M2 TAM in a sample isolated from the patient after erlotinib treatment, and then add the anti-avb3 antibody (e.g. LM609) in the treatment for patients with increased concentration of M2 TAM: because 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 erlotinib 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 the claims of Pat. 007, 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 Double Patenting rejection, Applicant argues:
Applicant respectfully requests that the double patenting rejections be held in abeyance until the resolution of allowable subject matter. However, Applicant notes that none of the '473 patent, the '007 patent, or the '057 Application remedy the deficiencies of Cheresh, Wu, and Zhang in rendering the claims obvious as outlined above.
Applicant’s arguments have been fully considered but they are not persuasive. Applicant is reiterating the arguments set forth above. Thus for the reasons set forth above the rejection is maintained.
It is noted that the Double Patenting rejections over Appl. 16/945,057 set forth in the Office Action of June 25, 2025 are withdrawn due to abandonment of Appl. 16/945,057.
Conclusion
No claims are allowed.
All other objections and rejections set forth in the previous Office Action of 06/26/2025 are hereby withdrawn in view of claim amendments and applicants’ arguments filed 09/25/2025.
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 CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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/CHENG LU/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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