DETAILED ACTION
This office action is in response to the Applicant’s filing dated May 19th, 2026.
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 .
Priority
This application is a 371 of PCT/US2021/047826 filed on August 26th, 2021; and has a PRO of 63/070,376 filed on August 26th, 2020.
Status of Claims
Claims 1-23 and 25-34 are pending in the instant application. Acknowledgement is made of Applicant’s remarks and amendments filed on May 19th, 2026. Acknowledgment is made of Applicant’s amendment of claim 23; cancelation of claim 24; and addition of new claims 26-34.
Election/Restrictions
Applicant’s election without traverse of Group III in the reply filed on May 19th, 2026 is acknowledged.
Claims 1-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 19th, 2026.
Applicant’s election of species without traverse of non-small cell lung cancer and pembrolizumab in the reply filed on May 19th, 2026 is acknowledged.
Claims 29-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 19th, 2026.
A prior art search was conducted for the elected species.
This search retrieved prior art.
In light of the prior art, and in the interest of compact prosecution, the Examiner expanded search to include all cancers.
Therefore, the Examiner’s search will not be extended unnecessarily in/for/during this Office action. Claims 23, 25-28 and 31-34 read on the elected species and will be examined herein for prior art purposes.
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 23, 25-28 and 31-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph because while being enabled for treating colon cancer in vivo in mice with Compound A and an anti-PD1 antibody, and the specification while showing a correlation of clinical benefits when Compound A and pembrolizumab are administered as a combination therapy on pages 30-32 in Example 7, do not reasonably provide enablement for treating all cancer. 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. This is a scope of enablement rejection.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention and breadth of the claims
The invention relates to a method of treating a patient having cancer.
Claims 23, 25-28 and 31-34 are directed to a method of treating a patient having cancer comprising administering Compound A and an immune checkpoint inhibitor. Thus, the claims are extremely broad with regards to the diseases to be treated, as well as the compounds that can be utilized.
2. The state and predictability of the art, and relative skill of those in the art
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain).
As illustrative of the state of the art, the examiner cites Gura et al (Science, New Series, (1997), 278(5340), 1041-1042), cited for evidentiary purposes, teaches that researchers face the problem of sifting through potential anticancer agents to find ones promising enough to justify human clinical trials. The reference further teaches that, since formal screening began in 1955, many thousands of drugs have shown activity in cell or animal models, but only 39 have actually been useful for chemotherapy (page 1041, first and second paragraphs). With regard to unpredictability, Johnson et al (British Journal of Cancer, (2001), 84(10), 1424-1431), also cited for evidentiary purposes, teaches that the in vivo activity of 39 different agents in a particular histology in a tumor model did not correlate with activity in the same human cancer (page 1426, Results). With regard to PD-1/PD-L1, Xu-Monette et al (Frontiers in Immunology; 03 December 2017; Volume 8; Article 1597), also cited for evidentiary purposes, teaches that “It is widely known that ligation of programmed cell death protein 1 (PD-1, also known as CD279) with PD-1 ligand 1 (PD-L1, also called B7-H1 or CD274) activates a critical immune checkpoint leading to T cell dysfunction, exhaustion, and tolerance. However, neither PD-1 nor PD-L1 expression is specific for the reversible T cell dysfunction state, and the effect of PD-1/PD-L1 blockade can be context-dependent. A large proportion of patients, including those with PD-1+/PD-L1+ expression, do not respond to PD-1/PD-L1 blockade. Some rational combination therapies have shown immune-related toxicities” (page 1, last paragraph; page 2, left column, first paragraph). “Like a tug-of-war, the actions of immune response and tumor development resist each other. PD-1 blockade may have antitumor effects in cancer patients but this is not always sufficient for a clinical response. Resistance mechanisms may come from either the immune system or the tumor” (page 16, right column, last paragraph). “Tumor PD-L1 expression through cell-intrinsic mechanisms may not have a significant role in driving immune suppression; PD-L1 and PD-L2 may also have costimulatory functions; and PD-1/PD-L1 blockade did not always elicit an effective antitumor response in preclinical studies. Moreover, although many anti-PD-1/PD-L1 clinical trials were remarkably successful which have revolutionized the treatment of cancer, some failed to reach the endpoint or resulted in an increased risk of death” (page 19, left column, first paragraph). With regard to TLR 7/8, Tran et al (Acta Biomaterialia, (2019), 94, 82-96), also cited for evidentiary purposes, teaches that “Toll-like receptors in cancer are considered a ‘‘double-edge” sword, which on the one hand, they can mediate the activation of innate immunity and then promote recruitment of immune cells to track and eliminate invading pathogens, including tumor cells. On the other hand, cancer often develops chronic inflammation via TLRs, which induces the anti-apoptotic effects of NF-kB, leading to tumorigenesis. These opposing effects are initiated by the fact that TLRs are expressed not only in immune cells but also in tumor cells. In addition, TLR agonists activate cytokine pathways that may cause chronic inflammatory and autoimmune diseases. Therefore, more comprehensive investigations in vitro as well as in vivo are needed to fully elucidate the involved mechanisms and choose appropriate dose regimes. Furthermore, the tumor immune microenvironment is complicated by the involvement of many immune factors, which can reduce treatment efficacy and promote tumor heterogeneity” (page 93, left column, first paragraph). Schmid et al (Nature Communications, (2017), 8(1), 1747, 1-12) teaches that R848, which is identical to instantly claimed Compound A, in combination with anti-PD1 antibodies have shown a delay in tumor growth and extended mouse survival in some embodiments, when administered to C57BL/6 mice that had been inoculated subcutaneously with MC38 colon cancer cells (page 8, Figure 7; page 9, left column, second paragraph).
“The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art” In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970).
Accordingly, the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statutory requirements. Furthermore, the mechanism of action of anticancer agents is often unknown or highly unpredictable, and the administration of such agents is frequently accompanied by undesirable side effects.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides data for showing a correlation of clinical benefits when Compound A and pembrolizumab are administered as a combination therapy on pages 30-32 in Example 7, but it is not sufficient to provide support for the full scope of all immune checkpoint inhibitors or conditions or disorders associated with all cancer.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed in supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that Compound A and an immune checkpoint inhibitor could be predictably used as treatment for all conditions or disorders associated with cancer, particularly in humans.
Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (42 USPQ 2d 1001, Fed. Circuit 1997). A review of the state of the art fails to reveal the mechanism of action or experimental data regarding the use of any claimed compounds to treat all cancer. Determining if any particular claimed compound would treat a conditions or disorders associated with cancer would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. As noted in supra, even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the inventions of claims 23, 25-28 and 31-34 do not comply with the scope of enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
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 23, 25-28, 31 and 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over Schmid et al (Nature Communications, (2017), 8(1), 1747, 1-12); as evidenced by BioLegend.com (https://www.biolegend.com/de-at/products/pe-anti-mouse-cd279-pd-1-antibody-6170 : 11 September 2014), cited for evidentiary purposes only.
Regarding claim 23, 25-27, 31 and 33-34, Schmid teaches the administration of R848 shown below:
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which is identical to instantly claimed Compound A, to C57BL/6 mice that had been inoculated subcutaneously with MC38 colon cancer cells. The mice were then treated with 60µg R848 administered intravenously in combination with 20µg anti-PD1 antibody 29F.1A12, which is a rat monoclonal antibody as evidenced by BioLegend.com (Page 1, Product Details) cited for evidentiary purposes only, every other day for a total of 10 injections in dosage forms that included free base compound combinations as well as nanoparticle (NP) formulations wherein the payload of R848 was contained in NPs with a surface conjugated with anti-PD1 29F.1A12 antibodies, disclosing a delay in tumor growth and extended mouse survival was observed in some embodiments (page 8, Figure 7; page 9, left column, second paragraph).
Schmid does not expressly disclose a dosage of 0.10 mg/m2 - 1.2 mg/m2.
It would have been prima facie obvious to one of ordinary skill in the art to utilize the amounts of R848 and anti-PD-1 antibody taught by Schmid as a starting point for optimizing the R848 and anti-PD-1 antibody amounts utilized to treat colon cancer since Schmid teaches R848 administered in combination with anti-PD-1 antibodies are useful for treating colon cancer and because dosage and treatment regimen are result-effective variables, i.e. a variable that achieves a recognized result. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Regarding claim 28, Schmid renders obvious the method of claims 23, 25-27, 31 and 33-34 as discussed in the above rejection.
Schmid further teaches that pembrolizumab is a fully humanized anti-PD-1 antibody that is approved for the treatment of cancer. Schmid discloses the use of pembrolizumab as the surface conjugated anti-PD1 antibody in nanoparticle (NP) formulations targeting human T cells; disclosing that the pembrolizumab-coated NPs demonstrated dose-dependent binding to human T cells (page 6, right column, first paragraph).
Schmid does not expressly disclose pembrolizumab as the anti-PD1 antibody used in combination with R848 to treat cancer.
It would have been prima facie obvious to one of ordinary skill in the art to utilize pembrolizumab as the anti-PD1 antibody used in combination with R848 to treat cancer in human subjects, because Schmid demonstrates therapeutic benefit in embodiments in which R848 is administered in combination with an anti-PD1 antibody and because Schmid explicitly identifies pembrolizumab as a humanized monoclonal antibody directed against the same PD-1 target. One of ordinary skill in the art would have reasonably expected pembrolizumab to perform the same known PD-1 blocking function in human subjects as the 29F.1A12 anti-PD1 antibody accomplished in murine models. The selection of pembrolizumab represents the substitution of one known anti-PD1 antibody for another, to perform the same established function, yielding no more than predictable results.
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Taken together, all of this would result in the methods of instant claims 23, 25-28, 31 and 33-34 with a reasonable expectation of success.
Conclusion
Claims 23, 25-28, 31-34 are rejected.
No claim is allowed.
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/C.L.J./Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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