DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
The Response to the Restriction/Election of Species Requirement mailed on October 22, 2025 has been entered. Applicant’s election of the invention of Group I (drawn to claims 1, 4, 9-10, 12-13, 16-19, 24-26, 28-29, and 41) in the reply filed December 9, 2025 is acknowledged. Applicant's election of the species of (1) an anti-EPHB2 blocking antibody as the specific agent/composition that decreases EPHB2 function and (2) immune checkpoint blockade (anti-PD-1/anti-PD-L1) as the specific immunotherapy in the same reply is also acknowledged. Because Applicant did not distinctly and specifically point out supposed errors in the restriction requirement, the election has been treated as an election without traverse. See MPEP § 818.01(a).
Claims 1, 4, 9-10, 12-13, 16-19, 24-26, 28-29, 33-35, 38, and 41, filed on December 19, 2022, remain pending. Claims 33-35 and 38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Claims 1, 4, 9-10, 12-13, 16-19, 24-26, 28-29, and 41 are under examination herein.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See ¶ 095. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term “NANOBODIES®”, which is a trade name or a mark used in commerce, has been noted in this application. See ¶ 0110. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9, 26, and 29 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 9 recites the limitation “…naïve to immunotherapy, has been previously treated by said immunotherapy, or has been treated by an immunotherapy other than said immunotherapy” in lines 2-4. There is insufficient antecedent basis for this limitation in the claim. Independent claim 1, from which claim 9 depends, earlier recites “an immunotherapy”, and it is unclear whether the immunotherapy recited in claim 9 is intended to refer to the immunotherapy of claim 1 or to an alternative immunotherapy.
Claim 26 recites the limitation “said enhancing immunotherapy” in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 26 depends, does recite “an immunotherapy” but does not recite “an enhancing immunotherapy.”
Claim 29 recites a listing of alternatives (a, b, c, or d), but the later described alternatives contain limitations that require an earlier alternative or alternatives recited by the claim. For example, considered by itself, item c (which recites “wherein said immune checkpoint blockade comprises…”) requires information from item b and would lack antecedent basis to claim 28 if the remaining alternatives were not listed. Furthermore, the claim as a whole appears to be drawn to a composition of matter (i.e., a kit) based on the preamble, but item c recites a method step (“administering a pharmaceutical composition”) for a process. Processes (which require at least one method step to be performed) constitute a separate statutory category of invention, and the appearance of elements of both in the claim render the intended scope of the claim unclear.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, 9-10, 12-13, 16-19, 24-26, and 41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating or ameliorating cancer by decreasing EPHB2 cancer cell function and administering to a subject in need thereof an immunotherapy, does not reasonably provide enablement for preventing cancer using the same steps. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The amount of guidance, direction, and exemplification disclosed in the specification, as filed, would not be sufficient to enable the skilled artisan to use the claimed invention at the time the application was filed without undue experimentation. MPEP § 2164.01 states: “The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).”
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors, which have been outlined in the Federal Circuit decision of In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), include, but are not limited to, the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed. See also Ex parte Forman, 230 USPQ 546 (BPAI 1986).
Nature of the invention / Breadth of the claims. The nature of the invention at issue is a method of preventing cancer in a subject in need thereof that comprises decreases EPHB2 function in a cell of said cancer and administering to the subject an immunotherapy, as set forth in claim 1 and its dependent claims.
It is noted that by virtue of claim 1 requiring the step of decreasing EPHB2 function in a cancer cell of the subject, the cancer cannot have been prevented beforehand.
State of the prior art / Predictability of the prior art. Clinical trials aimed at proving preventative cancer activity by a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossibly long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded cancer prevention trials with cancer incidence as an endpoint in all but a select few malignancies with treatments such as tamoxifen and finasteride (reviewed by Lee (2011) Nature Reviews Cancer 11: 211-218, at page 211; Cancer Prevention Overview (PDQ®)–Patient Version, National Cancer Institute).
Debela (SAGE Open Medicine (2021) 9: 20503121211034366) teaches that treating cancer has been a highly complex process, but that some therapeutic strategies have shown promise in patients. Conventional treatment approaches known in the field include surgery, chemotherapy, and radiotherapy (Abstract; page 2). More recent efforts have focused on the use of stem cell therapy, targeted drug therapy (e.g., monoclonal antibodies or small molecule inhibitors), gene therapy, and others (e.g., Abstract; pages 2-5). Debela further teaches that some combinatorial treatment strategies have been found to have a synergistic effect (page 1). To this end, Garcia-Aranda (International Journal of Molecular Sciences (2019) 20: 2296; cited in IDS) teaches that protein kinase inhibitors have been reported to enhance response to PD-1/PD-L1 blocking therapies (e.g., page 10).
Working examples / Guidance in the specification. Example 1 describes experiments in which melanoma or RCC cells with siRNA-mediated knockdown of EPHB2 were incubated in combination with TILs pre-incubated with an anti-PD-1 antibody (nivolumab). The disclosure states that EPHB2 knockdown increased specific killing in melanoma cells and RCC cells, which was not observed for anti-EPHB2 siRNA alone (e.g., ¶ 0134; Figure 1). Example 2 describes experiments in which melanoma cells or colon cancer cells were incubated with an anti-EPHB2 antibody and TILs pre-incubated with anti-PD-1 antibody (nivolumab). Said regimen also increased cancer cell killing (e.g., ¶ 0136-0137; Figures 2-3).
None of the working examples recited in the specification provide experimental evidence that the combination of instantly claimed steps is capable of preventing cancer in a subject. Accordingly, the specification lacks the critical elements necessary for illustrating a predictable response in a population of subjects for preventing cancer. Reasonable guidance with respect to preventing any disease relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to particular types of cancer such as melanoma, colon cancer, or renal cell carcinoma (RCC). The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of the diagnosis and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent.
Conclusion. Upon careful consideration of the factors used to determine whether undue experimentation is required, the amount of guidance, direction, and exemplification disclosed in the specification, as filed, is not deemed sufficient to have enable the skilled artisan to use the claimed invention to prevent cancer at the time the application was filed without undue and/or unreasonable experimentation.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 29 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim does not fall within at least one of the four categories of patent eligible subject matter because, as described in the rejection under 35 U.S.C. § 112(b) above, the claim appears to be drawn to a composition of matter but also contains a elements of a process (a separate statutory category) by reciting an active methodological step (“administering a pharmaceutical composition comprising an antibody that binds to and inhibits PD-1, …”) in item c. Claims that do not purport to recite one of a process, machine, manufacture, or composition of matter fail to comply with 35 U.S.C. § 101.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
Claims 1, 4, 10, 18-19, 24-26, and 41 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sennhenn (WO 2020/083909 A1; published April 30, 2020; cited in IDS).
Sennhenn discloses protein kinase inhibitors that are structurally similar to but functionally distinct from dasatinib, and pharmaceutical compositions thereof, as well as methods of using said inhibitors and/or compositions in the treatment of proliferative disorders (e.g., leukemia or solid tumors) alone or in combination with immune checkpoint inhibitors (e.g., Abstract; ¶ 1-35, 243; claims 1-6, 14-16, 19-22). Sennhenn discloses an exemplary protein kinase inhibitor “B3” which, like dasatinib (“A8”), inhibits the activity of EPHB2 to less than about 25% of residual activity (e.g., ¶ 13, 39; Figure 3; Examples 1-3). Sennhenn teaches a method of treating a proliferative disorder (e.g., a solid tumor, melanoma, colorectal cancer) by administering to a subject in need thereof a compound as illustrated in claim 1 (which inhibits the activity/expression of EPHB2) as well as an additional therapeutic agent (e.g., an anti-PD-1 antibody such as nivolumab), wherein the treatment comprises inhibiting EPHB2 and enhancing tumor response to anti-PD-1 immunotherapy (e.g., claims 1-6, 14-16, 19-22), anticipating claims 1, 4, 10, 18-19, 24-26, and 41.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4, 9-10, 12-13, 16-19, 24-26, 28-29, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Mao (US 2008/0254024 A1) in view of Garcia-Aranda (International Journal of Molecular Sciences (2019) 20(9): 2296; cited in IDS).
Mao discloses anti-EphB2 antibodies and immunoconjugates, compositions thereof, and methods of using the same for therapeutic and diagnostic applications (e.g., Abstract; ¶ 0010-0067). Relevant to claims 1, 4, 10, 12-13, 16-17, and 41, Mao discloses exemplary anti-EphB2 antibodies and immunoconjugates which reduce, inhibit, or block EphB2 activity in vitro or in vivo, such as by reducing or blocking EphB2 ligand binding to EphB2 (e.g., ¶ 0037; Examples 3-5 at ¶ 0424-0428). Mao provides use of an antibody of the invention for treating a cancer (e.g., a colorectal cancer, melanoma, renal carcinoma, and others) or killing a cancer cell by administering an anti-EphB2 antibody of the invention (e.g., ¶ 0037-0038, 0047-0062; Example 1). Mao illustrates that EphB2 mRNA is overexpressed in human cancer tissue relative to healthy tissue (e.g., Figures 2-4; Example 1 at ¶ 0419-0421). Mao further provides that antibodies of the invention may be used in combination with other compositions in a therapy, e.g., another antibody that also inhibits tumor growth, either separately or in the same formulation (e.g., ¶ 0365-0368). By administering the anti-EphB2 antibody to a subject in need thereof, the method would necessarily comprise or consist of contacting an EPHB2-expressing cancer cell in the subject and decreasing the function of EPHB2 in the EPHB2-expressing cancer cell.
Relevant to claims 28-29, Mao provides kits comprising a composition having one or more anti-EphB2 antibodies of the invention for use in the preparation of a therapeutic treatment for cancer, which further comprises instructions for administering the composition to a subject in need thereof (e.g., ¶ 0046-0052).
However, Mao does not expressly teach administering an immunotherapy (e.g., an anti-PD-1 antibody) in combination with an anti-EphB2 antibody of the invention.
Garcia-Aranda reviews the role of protein kinases that are most frequently altered in tumor cells and their potential utility to enhance response to existing immunotherapeutic treatments. Garcia-Aranda teaches that immunotherapies based on the use of anti-PD-1/anti-PD-L1 blocking antibodies have shown great promise in the treatment of many cancers including melanoma, renal cell carcinoma (RCC), and others by preserving the anti-tumor capacity of T cells, but that use of immunotherapy as a mono-therapy rarely has a response rate exceeding 40% (Abstract; Section 1). Accordingly, Garcia-Aranda contends that new treatment strategies are needed to improve the efficacy of PD-1/PD-L1 inhibitors (Section 1).
Garcia-Aranda notes that the presence of altered receptor kinases, including Eph receptors, is a common phenotype in tumor cells (e.g., Section 2; Table 2). Garcia-Aranda teaches that the effectiveness of the combination of kinase inhibitors and anti-PD-1/anti-PD-L1 therapy (e.g., the anti-PD-1 antibody nivolumab) has been explored in several studies and shown to improve median overall survival (e.g., Section 2; Table 4), relevant to claims 1, 18-19, 24-26, and 41.
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the combination cancer treatment method disclosed by Mao to include administering an immunotherapy (e.g., an anti-PD-1 antibody) based on the further teachings of Garcia-Aranda, and to generate a kit comprising both therapies for the purpose of treating cancer in a subject in need thereof. The skilled artisan would have been motivated to administer a anti-EPHB2 blocking antibody because Mao and Garcia-Aranda both teach that EPHB2 is overexpressed in many cancer tumors, and would further have been motivated to administer an anti-PD-1 or anti-PD-L1 blocking antibody because Garcia-Aranda teaches that anti-PD-1/anti-PD-L1 inhibiting antibodies have demonstrated promise in cancer treatment through their ability to restore T cells’ anti-tumor capacity and overcome tumor cell immune escape mechanisms. Further, Garcia-Aranda provides that the combination of an inhibitor of a protein kinase such as EPHB2 in combination with PD-1/PD-L1 blocking therapies has the capacity to enhance treatment response relative to anti-PD-1/anti-PD-L1 monotherapy. There would have been a reasonable expectation of success because each of these therapeutic options individually have been disclosed to be useful for the same purpose (i.e., treating a cancer), and “‘It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. See MPEP § 2144.06(I).
Further regarding claim 9, while Mao and Garcia-Aranda do not appear to expressly discuss whether a combination treatment of the disclosure may be practiced as a first line or second line treatment, it would have been obvious to treat a subject in need thereof in either case, as the subject has a clear need to be treated. Furthermore, since Garcia-Aranda teaches that co-administering a protein kinase inhibitor enhances the efficacy of anti-PD-1/anti-PD-L1 blocking therapies, one would be motivated to either use the combination treatment method in a subject naïve to immunotherapy (to produce an enhanced effect relative to anti-PD-1/anti-PD-L1 mono-therapy) or to enhance the efficacy of a previously administered anti-PD-1/anti-PD-L1 mono-therapy.
Claims 1, 4, 9, 12-13, 16-17, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Sennhenn (WO 2020/083909 A1; supra) as applied to claims 1, 4, 10, 18-19, 24-26, and 41 above, further in view of Mao (US 2008/0254024 A1; supra) and Barquilla (Annual Review of Pharmacology and Toxicology (2015) 55: 465-487; cited in IDS).
The teachings of Sennhenn are recited in the 35 U.S.C. § 102 rejection above.
However, Sennhenn does not teach administering an antagonistic anti-EPHB2 antibody as an EPHB2 inhibitor in the combination treatment methods of the invention.
The teachings of Mao, with respect to administering an anti-EPHB2 blocking antibody in combination with another antibody to treat cancers, are recited in the 35 U.S.C. § 103 rejection above.
Barquilla reviews the role of the Eph receptor tyrosine kinase family in disease states including cancer. Barquilla teaches that Eph inhibitory antibodies are among several types of molecules that can be used to interfere with Eph/Ephrin signaling (e.g., pages 475-478; Table 1). By contrast, Eph small-molecule antagonists target multiple Ephs and may target additional targets (e.g., Table 1). According to Barquilla, “Antibodies are particularly suitable for modulating the Eph/ephrin system, given their high binding affinity and specificity coupled with their long in vivo half-life” (page 477).
Based on the further teachings of Mao and Barquilla, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute an anti-EPHB2 blocking antibody in place of the EPHB2 inhibitor compound taught by Sennhenn in a combination treatment method for cancer. The skilled artisan would have been motivated to do so because, as taught by Barquilla, using an anti-EPHB2 antibody would be desirable because antibodies have higher binding affinity and specificity compared to small molecule antagonists, and furthermore, antibodies have a longer in vivo half-life. Mao provides a proof-of-concept that an anti-EPHB2 antibody may be administered in combination with another anti-tumor therapeutic antibody to effect a treatment for cancer. There would have been a reasonable expectation of success because the protein kinase inhibitor taught by Sennhenn and the anti-EPHB2 antibodies described by Mao and Barquilla have equivalent functions (inhibiting EPHB2 signaling) and may be used for the same desired purpose of treating cancer. Furthermore, as stated in MPEP § 2144.06(I), “‘It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”.
Further regarding claim 9, while Sennhenn, Mao, and Barquilla do not appear to expressly discuss whether a combination treatment of their respective disclosures may be practiced as a first line or second line treatment, it would have been obvious to treat a subject in need thereof in either case, as the subject has a clear need to be treated. Furthermore, since Sennhenn teaches that co-administering a protein kinase inhibitor enhances the efficacy of an anti-PD-1 blocking therapy, one would be motivated to either use the combination treatment method in a subject naïve to immunotherapy (to produce an enhanced effect relative to anti-PD-1/anti-PD-L1 mono-therapy) or to enhance the efficacy of a previously administered anti-PD-1/anti-PD-L1 mono-therapy.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm EST.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643