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 .
Claim Status
As of the Non-Final Office Action mailed 6/12/2025, claims 15-16 and 19-31 were pending and claims 25-31 were withdrawn for being drawn to non-elected invention.
In Applicant's Response filed on 11/11/2025, claims 15-16 and 19-24 were amended.
As such, claims 15-16 and 19-31 are pending and claims 15-16 and 19-24 have been examined herein.
Withdrawn Objections/Rejections
The objection of record to claim 19 for minor informalities has been withdrawn in view of Applicant’s amendment.
The rejection of record of claims 15-16 and 19-24 under 35 USC § 112(b) have been withdrawn in view of Applicant’s amendment to claim 15.
The rejection of record of claim 15-16 and 19-24 under 35 USC § 112(a) have been withdrawn in view of Applicant’s amendment to the claims.
Maintained Rejections
Applicant's arguments regarding the 101 rejection of record have been fully considered but they are not persuasive. The rejection has been maintained and has been recast below and modified to account for Applicant’s amendments to the claims. Response to arguments will follow the rejection.
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.
Claims 15-16 and 19-24 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to at least one judicial exception (natural correlation/natural phenomena and abstract idea) without significantly more. This judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
Step 1 (Statutory Category): This part of the eligibility analysis evaluates whether the claims fail within any statutory category. Here, the claims recite, inter alia, a method for measuring anti-cancer activity of one or more immune checkpoint inhibitor(s), comprising grafting tumor cells in an embryonated bird egg model, wherein the embryonated bird egg model excludes the presence of immune effector cells other than those of the grafted egg. This is a method/process; therefore, the claims fall within a statutory category of invention. [Step 1: YES]
Step 2A (Judicial Exceptions), Prong 1: This part of the eligibility analysis evaluates whether the claim recites a judicial exception. A claim “recites” a judicial exception when the exception is “set forth” or “described” in the claim (see MPEP 2106.04(II)). The claims recite at least one judicial exception. The claims provide a description of the natural correlation between immune checkpoint inhibitors and measuring their anti-cancer abilities. Selecting and measuring immune checkpoint inhibitors with anti-cancer activity as in claim 15 and 16, requires a mental step (an abstract idea) because the measuring and treatment step requires drawing a conclusion from the comparison between different checkpoint inhibitors’ anti-cancer activity during data gathering (also as in claim 23). Claim 19 recites, inter alia, measuring the effect of the immune checkpoint inhibitors administered on the tumorigenesis of the tumors developed in the grafted embryo. Claim 19 (and claims dependent therefrom) also requires a mental comparison between different checkpoint inhibitors’ anti-cancer activity during the data gathering step via the investigation step. Thus, the claims recite at least two judicial exceptions: a natural correlation and abstract idea. [STEP 2A, Prong 1: YES].
Therefore, the analysis proceeds to Step 2A Prong 2.
Step 2A (Judicial Exceptions), Prong 2: This part of the eligibility analysis evaluates whether the claims as a whole integrate the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claims beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claims as a whole integrate the exception into a practical application. In addition to the judicial exceptions, the claims also recite steps for creating a grafted tumor bird egg model, administering the checkpoint inhibitors to the grafted model, incubation and collection steps, and the parameters in which tumorigenesis could be investigated. These steps are data acquisition that does not integrate the judicial exception into practical application. They are considered to be insignificant extra-solution activity (see MPEP 2106.05(g)). Note that the immune checkpoint inhibitor selection are part of the judicial exception. The measuring and treating steps based on comparing tumorigenesis (growth, inflammation, immune infiltration, angiogenesis, etc.) is also merely an instruction to “apply” the judicial exception in a generic way per claim 15 and 16 and fails to integrate the JE into a practical application. Claim 19 requires grafting tumor cells into the CAM of an embryonated egg and incubating the embryonated egg after administration of the immune checkpoint inhibitors for at least 4 days and at most 12 days, which is solely part of data gathering. As previously stated, the broad step of investigating the effects of the immune checkpoint inhibitors requires a mental comparison of the immune checkpoint inhibitors and has no meaningful application of the judicial exception beyond generic analysis. Dependent claims 20-24 also fail to integrate the JE into a practical application. Furthermore, a judicial exception cannot form the basis for integration, so it cannot be considered to integrate the natural correlation into a practical application. See MPEP 2106.04(d)(III), which states that “Because a judicial exception alone is not eligible subject matter, if there are no additional claim elements besides the judicial exception, or if the additional elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application.” [STEP 2A, Prong 2: NO]
Step 2B (Significantly More): This part of the eligibility analysis evaluates whether the claims as a whole amount to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim (see MPEP 2106.05). This is based on an additional consideration of whether the elements in addition to the judicial exception add beyond what was well-understood, routine, and conventional to the claims. The present claims require the engraftment of tumor egg cells into an embryonated bird egg model. The creation of such a model is routine, well-understood, and conventional in the art.
Chen et al (J Cell Biochem. 1 Aug 2007; 101(5):1316-1327; Ref. A of Non-Patent Literature in IDS filed 16 Nov 2021; hereinafter “Chen”; previously cited) evidences the growth of aggressive human breast cancer cells in an embryonated chicken egg at one site on the CAM of the chicken embryo (p. 1318, “Growth of cancer cells on the chick chorioallantoic membrane”). The eggs were also seeded with or without 600 micrograms of recombinant rtEa4-peptide to assess its cancer inhibitive qualities (same para). Cells seeded together with 600mg of rtEa4-peptide did not grow into tumor mass (p.1320, col 2) and the invasiveness of the cancer cells was inhibited by the peptide (p. 1322, col 1).
Claim 16 requires the selection of an immune checkpoint inhibitors with the most promising anti-cancer activity for the treatment of the tumor developed in the model. The selection of a better anti-tumor therapy is routine, well-understood, and conventional in the art and does not amount to significantly more than the judicial exception. The investigative step of claim 19 is also routine, well-understood, and conventional and does not amount to significantly more than the judicial exception. Claims 20 and 21 include incubation time and tumor collection steps, which appear to be merely routine and conventional without adding significantly more to the JE. While claim 22 elaborates on how the investigation step of claim 19 could occur through, inter alia, “measuring parameters such as tumor growth, metastatic invasion, angiogenesis, neo-angiogenesis,” etc., these assays are also routine and conventional. Claim 23 does not amount to significantly more than the judicial exception recited in claim 19 as it only describes another avenue through which evaluating tumorigenesis could occur (through tumor comparison between egg models). Finally, claim 24 does not recite anything significantly more than the judicial exception as it only clarifies where the tumor cells used in the data gathering are derived from.
Fessas et al (Semin Oncol, 4 Jul 2017; 44(2):136-140; Ref. E of Non-Patent Literature in IDS filed 16 Nov 2021; hereinafter “Fessas”; previously cited) evidences that two anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, should be considered clinically interchangeable based on clinical data for targeted cancer therapy (p. 136, “Introduction” para 1). Both antibodies were, when tested, were able to stimulate IFN-gamma responses in cancer patients (p. 139, col 1 para 2). The reference also evidences the assessment of both antibodies in murine tumor models and showed similar effectiveness in colon adenocarcinoma, with nivolumab showing 76% growth inhibition at day 20 and pembrolizumab showing tumor growth inhibition of 92.5% at day 20 (p. 139, col 1, para 3).The art demonstrates that avian egg models of cancer, screening immune checkpoint inhibitors for use as immunotherapy against cancer, and identifying the “most promising candidate” of the known immune checkpoint inhibitors would have been routine and conventional in the art. The claims recite use of the immune checkpoint inhibitors to see if they modulate, for example, tumor angiogenesis and growth, at a high level of generality, thus Applicant is relying on the conventional and well-understood use of immune checkpoint inhibitors, incubation and grafting step, the selection process, and investigative steps as instantly claimed that are directly informed by the judicial exception, and therefore are not evidence of additional features over the judicial exception itself. [STEP 2B: NO]
In view of the above, the claims are considered to be directed to the judicial exception without integration into a practical application, or adding significantly more to the claim over the judicial exception. Therefore, the claims do not qualify as eligible subject matter under 35 USC § 101.
Response to Arguments
Applicant first argues on p. 15-22 of Remarks that the effect of manmade therapeutics cannot be a judicial exception because the immune checkpoint inhibitors claimed are not naturally occurring. Applicant also argues that the specification contains appropriate measurements such as measuring tumor weight, expression of markers, histological analysis, etc. to evaluate toxicity on the tumor. Applicant argues that these measurement cannot be performed by the human mind and require the use of tools and scientific instrument. Applicant also argues that the analysis fails at 2A prong 2 because the steps of grafting, administering, incubation, and collection are physical steps that are integrated into a practical method.
In response, the examiner reminds Applicant that the 101 rejection is not for a product of nature; rather, the natural correlation/natural phenomena is between the immune checkpoint inhibitor molecules (manmade or not) and their subsequent therapeutic effect on a grafted tumor. Put simply, at a minimum, Applicant’s judicial exception is making an observation on how a drug effects cancer (i.e., drawing a line between a drug and its effects (known or otherwise)). Second, observations of tumor effect (even if requiring additional tools) can still be done by the human mind. As previously explained, the claims are directed to at least one judicial exception (natural correlation/natural phenomena and abstract idea) without significantly more. Claims recite a mental process when they contain limitations that can practically be performed in the human mind, including for example, observations, evaluations, judgments, and opinions (see MPEP 2106.04(a)(2)(III)(A)). Examples of claims that recite mental processes include a claim to "collecting information, analyzing it, and displaying certain results of the collection and analysis," where the data analysis steps are recited at a high level of generality such that they could practically be performed in the human mind, Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016); claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014); a claim to collecting and comparing known information (claim 1), which are steps that can be practically performed in the human mind, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011), etc.
The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation. See, e.g., Benson, 409 U.S. at 67, 65, 175 USPQ at 674-75, 674 (noting that the claimed "conversion of [binary-coded decimal] numerals to pure binary numerals can be done mentally," i.e., "as a person would do it by head and hand."); Synopsys, Inc. v. Mentor Graphics Corp., 839 F.3d 1138, 1139, 120 USPQ2d 1473, 1474 (Fed. Cir. 2016) (holding that claims to a mental process of "translating a functional description of a logic circuit into a hardware component description of the logic circuit" are directed to an abstract idea, because the claims "read on an individual performing the claimed steps mentally or with pencil and paper"). Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer. As the Federal Circuit has explained, "[c]ourts have examined claims that required the use of a computer and still found that the underlying, patent-ineligible invention could be performed via pen and paper or in a person’s mind." Versata Dev. Group v. SAP Am., Inc., 793 F.3d 1306, 1335, 115 USPQ2d 1681, 1702 (Fed. Cir. 2015). The measuring and investigation steps are recited at a high level of generality, encompassing (at a minimum) observing tumor size change and mentally noting anti-tumor effect, weighing tumor sample pre- and post-treatment and mentally comparing changes to determine effect on tumor growth/size, etc.
Furthermore, as explained in the rejection above, creating a grafted tumor bird egg model, administering the checkpoint inhibitors to the grafted model, incubation and collection steps, and the parameters in which tumorigenesis could be investigated. These steps are data acquisition that does not integrate the judicial exception into practical application. The examiner notes that the data gathering steps here are what inform the JE (i.e., these steps are done and the results of these steps are used to determine effect on tumor via observations, evaluations, etc.). Thus, contrary to Applicant’s assertion, the measurement steps that occur do, in fact, matter particularly since Applicant is claiming “measuring anti-cancer activity.”
Since the treatment, measuring, and investigation steps are recited at such a high level of generality, the claims fail to impose meaningful limits upon the judicial exceptions themselves. The other steps recited in the method are well-understood, routine, and conventional such that they do not integrate the judicial exception into a practical application. Thus, the rejection is proper.
New Grounds of Rejections Necessitated by Amendments
Examiner’s Note
Please note that Applicant’s amendments to the instant claims broadens the scope of the claims to include immunodeficient and partially immune competent CAM models necessitates new grounds of prior art rejections.
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.
Claim(s) 15-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Goldstein et al (US9273338B2, 12/3/2012; published 3/1/2016) in view of Shipp et al (WO2015013389A2, 7/23/2014; published 1/29/2015).
Goldstein teaches a method for screening anti-cancer drugs, comprising engrafting a population of malignant mammalian hematopoietic cells into a turkey egg, wherein at least a portion of the malignant mammalian hematopoietic cells are engrafted into at least one hematopoietic tissue of the turkey egg selected from the group consisting of bone marrow, spleen, and liver; exposing the malignant mammalian hematopoietic cells to at least one test drug; and analyzing the population of hematopoietic tissue engrafted cells after a determined period of time; thereby screening anti-cancer drugs for hematopoietic malignancies (see claim 1 of Goldstein) (“method for measuring anti-cancer activity . . . , comprising grafting tumour cells on chorioallantoic membrane (CAM) of an embryonated bird egg, without addition of immune effector cells other than those generated by the grafted egg; and measuring anti-cancer activity” as in instant claim 15 in-part).
The difference between the instant invention and Goldstein is that it does not teach that the anti-cancer drug is an immune checkpoint inhibitor selected from among an anti-PD1, an anti-PDL1, and an anti CTLA-4 antibody.
Shipp teaches an immunogenic composition further comprising at least one additional immunostimulatory agent (see claim 12-13 of Shipp). The reference teaches that the immunostimulatory agent is an immune checkpoint inhibitor selected from the group consisting of PD-1, PD-L1, . . . , CTLA-4 (“wherein the one or more immune checkpoint inhibitor(s) is selected from among an anti-PD1, an anti-PDL1, and an anti CTLA-4 antibody” as in instant claim 15 in-part). The reference also teaches that the chicken chorioallantoic membrane (CAM) assay is suitable for showing anti-angiogenic activity of the composition in both normal and neoplastic tissues (same para). This shows that immunogenic compositions including immune checkpoint inhibitors can be screened in a CAM model.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to screen anti-cancer therapies using a CAM assay as taught by Goldstein, where the anti-cancer therapies are immune checkpoint inhibitors as taught by Shipp, to arrive at the instantly claimed invention. One of ordinary skill would have been motivated to use the CAM model of Goldstein to screen immune checkpoint inhibitors as in Shipp with a reasonable expectation of advantageously showing anti-angiogenic activity in the neoplastic tissues as taught by the prior art.
Regarding claim 16, the combination of Goldstein and Shipp render prima facie obvious “wherein the method further comprises treating a tumour developed from the tumour cells grafted into the embryonated egg with the immune checkpoint inhibitor(s) having anti-cancer activity from among the immune checkpoint inhibitors evaluated” as in instant claim 16.
Claim(s) 19-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Goldstein in view of Shipp as applied to claims 15-16 above, and further in view of Li et al (J Vis Exp. 2015 Oct 9;(104):52411).
The difference between Goldstein and Shipp in combination and the instant invention is that they do not teach wherein the grafting of tumour cells is carried out on the CAM of the embryonated bird egg that has been incubated up to a stage of development corresponding to CAM formation and equivalent to at least 9 days of development in a chicken embryo, and the method further comprising: administering the immune checkpoint inhibitor(s) into the embryonated egg at least 24 hours after grafting, investigating an effect of the immune checkpoint inhibitor(s) thus administered on tumorigenesis of tumors developed in the grafted egg, incubating the embryonated egg once grafted for at least 4 days and at most 12 days, after first administering the immune checkpoint inhibitor(s) into the grafted embryonated egg before investigating measuring the effect on tumorigenesis (as in instant claim 19).
Li teaches chick chorioallantoic membrane (CAM) begins to develop by day 7 after fertilization and matures by day 12 (abstract). The CAM is naturally immunodeficient and highly vascularized, making it an ideal system for tumor implantation (same para). Furthermore, the CAM contains extracellular matrix proteins such as fibronectin, laminin, collagen, integrin alpha(v)beta3, and MMP-2, making it an attractive model to study tumor invasion and metastasis (same para). The reference describes a protocol that achieved chick embryonic survival rates of up to 93% with extremely high tumor engraftment (Introduction, para 3). First, 8-day old embryonated eggs are obtained, then incubated for 48 hours (i.e., until 10 days old) (Egg Incubation, step 1-2). The CAM of the egg is then dropped and inoculated with tumor cells. Cells can be treated with drugs or other test agents as needed for experiments by resuspending into the cell/basement membrane mixture suspension. Alternatively, agents can be pipetted onto the cell/basement membrane mixture suspension after grafting. The tumor is allowed to grow for 5 to 7 days (“the method further comprises incubating the embryonated egg once grafted for at least 7 days after first administering . . . into the grafted embryonated egg before investigating measuring the effect on tumorigenesis” as in instant claim 20). This reads on “grafting of tumour cells is carried out on the CAM of the embryonated bird egg that has been incubated up to a stage of development corresponding to CAM formation and equivalent to at least 9 days of development in a chicken embryo . . . incubating the embryonated egg once grafted for at least 4 days and at most 12 days, after first administering the . . . into the grafted embryonated egg before investigating measuring the effect on tumorigenesis” as in instant claim 19 in-part (please note that the combination of Goldstein and Ship render obvious the use of immune checkpoint inhibitors and investigation steps of instant claim 19). The reference further discusses how to harvest the tumors post-incubation (Harvesting Tumors, steps 1-4) (“wherein the method further comprises collecting the tumors which develop from the grafted tumour cells at the end of incubation of the embryonated egg after administering” as in instant claim 21).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to screen anti-cancer immune checkpoint inhibitors using a CAM assay as taught by Goldstein and Shipp in combination, where the embryonated egg is 10 days old before grafting as taught by Li, to arrive at the instantly claimed invention. Li shows the successful creation of a CAM model on a 10 day-old embryonated egg. One of ordinary skill would have been motivated to modify the method of screening as taught by Goldstein and Shipp in combination to include the steps of Li with a reasonable expectation of advantageously having a CAM model that has a 93% survival rate and high tumor engraftment as taught by the prior art. One of ordinary skill would recognize that the improvements taught in Li would improve similar CAM models in a similar way.
Regarding claim 22, Shipp teaches that the level of angiogenesis inhibition may be determined using methods well known in the art, including counting the number of blood vessels and/or the number of blood vessel branch points (para 10 of Definitions). Art-accepted in vivo assays are also known, and involve the use of various test animals such as chickens, rats, mice, rabbits and the like. These in vivo assays include the chicken chorioallantoic membrane (CAM) assay, which is suitable for showing anti-angiogenic activity in both normal and neoplastic tissues (same para) (“wherein investigating tumorigenesis comprises measuring one or more parameters selected from among . . . angiogenesis, neo- angiogenesis” as in instant claim 22).
Regarding claim 23, Goldstein teaches that a positive outcome is determined when said test drug reduces at least 50% of the engrafted cells compared to untreated grafts (see claim 8 of Goldstein) (“wherein the anti-cancer activity comprises measuring tumorigenesis of tumors collected after administering the immune checkpoint inhibitor(s) in the embryonated egg once grafted with that of tumors collected in an embryonated egg of the same bird previously grafted according to a same method with same tumour cells in which no immune checkpoint inhibitor has been administered” as in instant claim 23).
Regarding claim 24, Goldstein teaches that the population of malignant mammalian hematopoietic cells is a population of malignant human hematopoietic cells obtained from a subject having a hematopoietic neoplastic disorder and the determined period of time is between 1 and 30 days of incubation (see claim 3-4 of Goldstein).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GILLIAN C REGLAS whose telephone number is (571)270-0320. The examiner can normally be reached M-F 7-3.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632