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Patent Application 17797660 - DIAGNOSTIC AND PROGNOSTIC UTILITY OF EXOSOMES IN - Rejection

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Patent Application 17797660 - DIAGNOSTIC AND PROGNOSTIC UTILITY OF EXOSOMES IN

Title: DIAGNOSTIC AND PROGNOSTIC UTILITY OF EXOSOMES IN IMMUNOTHERAPY

Application Information

  • Invention Title: DIAGNOSTIC AND PROGNOSTIC UTILITY OF EXOSOMES IN IMMUNOTHERAPY
  • Application Number: 17797660
  • Submission Date: 2025-05-16T00:00:00.000Z
  • Effective Filing Date: 2022-08-04T00:00:00.000Z
  • Filing Date: 2022-08-04T00:00:00.000Z
  • National Class: 435
  • National Sub-Class: 007230
  • Examiner Employee Number: 79112
  • Art Unit: 1641
  • Tech Center: 1600

Rejection Summary

  • 102 Rejections: 3
  • 103 Rejections: 0

Cited Patents

The following patents were cited in the rejection:

Office Action Text


    
DETAILED ACTION

1.  The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .

2  Applicant's amendment, filed on 01/12/2023, is acknowledged.

3.  Claims 1-4, 7-21 and 40 are pending.

4.  Applicant’s IDS, filed 11/18/2022, is acknowledged. 
 
5. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA  35 U.S.C. 112, first paragraph):
(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.

 
6.  Claims 1-4 and  7-20 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 pre-AIA  the inventor(s), at the time the application was filed, had possession of the claimed invention.  

Claim 1 encompass a genus of immune checkpoint blockade (ICB) therapy in the treatment of a subgenus of cancer subjects having B-cell exosomes, cancer subjects having an increase in the amount of B-cell exosomes or cancer subjects having an amount of B-cell exosomes that is not significantly different than a control.

Claim 7 encompasses a broad genus of anticancer treatments in the treatment of a subgenus of cancer subjects having B-cell exosomes, cancer subjects having an increase in the amount of B-cell exosomes or cancer subjects having an amount of B-cell exosomes that is not significantly different than a control.

Claim 8 encompasses a genus of anticancer treatment for a genus of cancers including surgical therapy, chemotherapy, radiation therapy, hormonal therapy, immunotherapy, small molecule therapy, receptor kinase inhibitor therapy, anti-angiogenic therapy, cytokine therapy, cryotherapy or a biological therapy.

Claim 9 encompasses a genus ICB monotherapies or a combination ICB therapy.

Claim 10 encompasses a genus of inhibitors of PD-1, PDL1, PDL2, CTLA-4, B7-1, and/or B7-2.

Claim 11 encompasses a genus of anti-PD-1 monoclonal antibody and/or a genus of anti-CTLA-4 monoclonal antibody.

However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of treating cancers having B-cell exosomes.  The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, Âś 1 "Written Description" Requirement make clear that 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 genus.

The claims are not supported by a description that satisfies 35 U.S.C. § 112, first paragraph. "[T]he test for sufficiency [of the written description] is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc).

A "sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Id.
at 1350. "[ A ]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials." Id.

"[F]unctional claim language can meet the written description requirement when the art has established a correlation between structure and function." Id. "But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species." Id.

The written description standard set out in Ariad applies to antibodies. See Amgen, Inc. v. Sanofi, 872 F.3d 1367, 1376-79 (Fed. Cir. 2017) ( applying the Ariad standard to antibodies claimed based on their binding and blocking activities); Abb Vie Deutschland GmbH & Co. v. Janssen
Biotech, Inc., 759 F.3d 1285, 1298-1300 (Fed. Cir. 2014) (same).

The claims here are directed to methods of using antibodies, rather than the antibodies themselves, but the same standard applies with regard to the written description requirement. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916,926 (Fed. Cir. 2004):

Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.

In University of Rochester, the "claimed method depend[ed] upon finding a compound that selectively inhibits PGHS-2 activity. Without such a compound, it is impossible to practice the claimed method of treatment." Id. ( citation omitted). Similarly here, the claimed methods cannot be practiced without antibodies having the inhibiting or blocking activities recited in the claims. Appellant's argument that the claims are adequately described because they are directed to a method, not a composition of matter, is therefore unpersuasive.

 While the specification at [0051] discloses nivolumab (PD-1), pembrolizumab (PD-a), pidilizumab (PD-1), ipilimumab (CTLA-4) and tremeliumab (CTLA-4). The PDL1 inhibitor comprises AMP- 224. Nivolumab, also known as MDX-1106-04, MDX- 1106, ONO-4538, BMS-936558, and OPDIVOÂŽ, is an anti-PD-1 antibody described inW02006/121168. Pembrolizumab, also known as MK-3475, Merck 3475, lambrolizumab, KEYTRUDAÂŽ, and SCH-900475, is an anti-PD-1 antibody described in W02009/114335. Pidilizumab, also known as CT-011, hBAT, or hBAT-1, is an anti-PD-1 antibody described in W02009/101611. AMP-224, also known as B7-DCIg, is a PDL2-Fc fusion soluble receptor described in WO2010/027827 and WO2011/066342. Additional PD-1 inhibitors include MEDIO680, also known as AMP-514, and REGN2810. The specification discloses that ICB therapy comprises a PDL1 inhibitor such as Durvalumab, also known as MEDI4736, atezolizumab, also known as MPDL3280A, avelumab, also known as MSB00010118C, MDX-1105, BMS-936559, or combinations. The ICB therapy comprises a PDL2 inhibitor such as rHIgM12B7. [0053] In some embodiments, the inhibitor comprises the heavy and light chain CDRs or VRs of nivolumab, pembrolizumab, or pidilizumab [0052]. The anti- CTLA-4 antibodies disclosed in: US 8,119,129, WO 01/14424, WO 98/42752; WO 00/37504 (CP675,206, also known as tremelimumab; formerly ticilimumab) [0056]. [0047] Embodiments of the disclosure may include administration of immune checkpoint  blockade therapy, which are further described below. 1. PD-1, PDL1, and PDL2 inhibitors.  It is unclear which, if any, of the functional limitations in the claims are purportedly met by the antibody described in the specification but, in any event, written descriptive support depends on "whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad, 598 F.3d at 1351 (emphasis added).  Applicant has not provided evidence that the listed antibodies have the specific inhibiting or blocking properties required by the claims which treat each and every cancer subject having B cell exosome detected in the sample.

The instant case is akin to the Federal Circuit applied this rubric in Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330 (Fed. Cir. 2021). The asserted claims in Juno were drawn to a nucleic acid polymer encoding a chimeric antigen T-cell receptor (CAR T-cell) comprising three segments: an intracellular signaling segment, a co-stimulatory segment comprising a specific amino acid sequence, and a binding segment (scFv). Id., at 1334. Juno’s specification disclosed two exemplary scFvs that bind to specific targets (CD19 and PSMA). Id., at 1333. Juno argued that other scFvs were known in the art, and that scFvs were interchangeable components with a shared, common structure. Id., at 1336. The Federal Circuit acknowledged that scFv sequences were known in the art, and that scFvs share a common structure (seemingly satisfying the common structural features rubric), but nevertheless concluded that Juno’s specification lacked written description. The court stated:

[T]he written description of the ’190 patent discloses only two scFvexamples and provides no details regarding the characteristics,sequences, or structures that would allow a person of ordinary skillin the art to determine which scFvs will bind to which target. ThatscFvs in general were well-known or have the same generalstructure does not cure that deficiency.

Juno at 1339-1340. In other words, as the court stated: “For the claimed functional scFv genus, the ’190 patent does not disclose representative species or common structural features to allow a person of ordinary skill in the art to distinguish between scFvs that achieve the claimed function and those that do not.” Id. at 1342.

An abundance of literature shows that the combination of an immune checkpoint inhibitor (e.g., an-anti-PD-1) in combination with another anti-cancer agent does not generally yield desired result.  For example, Dolgin (CANCER DISCOVERY, AACRJournals.org MAY 2023, pages-1033 1023) teach that late-stage trials evaluating the PD-1 inhibitor pembrolizumab in men with prostate cancer have all ended in failure, leading clinicians to conclude that new treatment strategies are needed to help make checkpoint blockade more effective in the immune-suppressed environment of most prostate tumors.  Over and over, trials evaluating PD-1/PD-L1 inhibitors in advanced prostate cancer have missed the mark. The failures have led to questions as to why—and have prompted oncologists to conclude that new treatment strategies are needed.  Two phase III trials of the PD-1 inhibitor pembrolizumab (Keytruda; Merck) were halted earlier this year after interim analyses showed that adding it to the antiandrogen drug enzalutamide (Xtandi; Astellas) and androgen deprivation therapy (ADT) failed to extend survival compared with placebo plus enzalutamide and ADT in men with metastatic castration-resistant prostate cancer (mCRPC; KEYNOTE-641) or metastatic hormone-sensitive disease (KEYNOTE-991).  Trials for mCRPC evaluating pembrolizumab plus docetaxel and pembrolizumab plus the PARP inhibitor olaparib (Lynparza; AstraZeneca)—KEYNOTE-921 and KEYLYNK-010, respectively—had previously come up short as well.  A team co-led by Russell Pachynski, MD, of Washington University School of Medicine in St. Louis, MO, previously showed that nivolumab plus docetaxel has clinical activity in men with chemotherapy-naive mCRPC (Eur J Cancer 2022;160:61–71). But expectations for success are diminishing, especially when factoring in last year's report that another inhibitor of the same pathway—the PD-L1 blocker atezolizumab (Tecentriq; Genentech)—offered no survival benefits over placebo when added to enzalutamide in a phase III mCRPC trial (Nat Med 2022;28:144–53) (see the entire reference).

McGrail et al (Ann Oncol. 2021, 32(5):661-672) teaches hat high tumor mutation burden fails to predict immune checkpoint blockage response across all cancer types. McGrail et al analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type-specific studies are warranted.

Broderick, JM. (Urology Times, Oct. 30, 2020) teach a strategy of upfront nivolumab (Opdivo) followed by response-dependent sequential use of ipilimumab (Yervoy) did not provide a benefit in patients with advanced renal cell carcinoma (RCC), according to findings from the phase 2 OMNIVORE trial published in the Journal of Clinical Oncology.

Nyberg K., (ILCN, on: January 28, 2021, In: Presidential Symposium, WCLC 2020 Archive ) teach dual PD-1 and CTLA-4 checkpoint blockade confers no therapeutic benefit beyond PD-1 blockade alone in PD-L1–positive NSCLC.

The specification describes the immune checkpoint blockade (ICB) therapy as an agent (e.g., an inhibitor of PD-1, PDL1, PDL2, CTLA-4, B7-1, and/or B7-2 [0012]) and treat cancer (e.g., a skin cancer,  basal-cell skin cancer, squamous-cell skin cancer, melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, ketoacanthoma, spindle cell tumors, sebaceous carcinomas, microcystic adnexal carcinoma, Paget's disease of the breast, atypical fibroxanthoma, leiomyosarcoma, or angiosarcoma. In some embodiments, the cancer comprises melanoma, metastatic melanoma, Lentigo Maligna, Lentigo Maligna Melanoma, Superficial Spreading Melanoma, Nodular Melanoma, Acral Lentiginous Melanoma, Cutaneous Melanoma, or Desmoplastic Melanoma [0010]).   

While the amino acid sequence of PD-1, PDL1, PDL2, CTLA-4, B7-1, and B7-2, the specification does not describe any correlation between the sequence and the structure of any ICB inhibitor that treat cancer subject after B-cell exosomes have been detected in a biological sample from the subject. 

The specification describes a method of screening antibodies for treating cancer subject B-cell exosomes have been detected in a biological sample from the subject (see [0056]), however, there is no information regarding what structural features would likely be associated with such the treatment cancer subject after B-cell exosomes have been detected in a biological sample from the subject.  Thus, the specification does not disclose a correlation between an ICB inhibitor for treat cancer subject after B-cell exosomes have been detected in a biological sample from the subject and the structure of a putative ICB inhibitor. 

The disclosure does not allow one of skill in the art to visualize or recognize the structure of any ICB inhibtors required to practice the claimed method.  Accordingly, one of ordinary skill in the art would conclude that the applicant would not have been in possession of the claimed method of using an ICB inhibitor that treat cancer subject after B-cell exosomes have been detected in a biological sample from the subject because an ICB inhibitor possessing the desired activity required to practice the method is not adequately described and was not known in the art.

The USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018.  
     See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf.

The Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies, including the following.
     “In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”.

In contrast to applicant’s reliance of describe the epitope of the PD-1, PDL1, PDL2, CTLA-4, B7-1, and B7-2 in providing a fully characterized antigen / specific epitope as well as claiming structural elements of the antigen, one or more functions recited in the claims and binding affinity, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed anti- PD-1, PDL1, PDL2, CTLA-4, B7-1, and B7-2 antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).

There is no evidence that knowledge of the chemical structure of an antigen gives the required kind of structure identifying information about the corresponding antibodies Applicants attempt to describe the invention by describing something that is not the invention: viz., the antigens to which the antibodies may bind.   There nothing in the disclosure that describes the antibodies as required by the test set forth in Ariad.

However, the anti-PD-1, PDL1, PDL2, CTLA-4, B7-1, and B7-2 antibodies are required to practice the invention.  The specification also fails to provide any specific structural or physical information so as to define a genus of antibodies having the desired therapeutic properties. Applicant is merely relying on the identification of PD-1, PDL1, PDL2, CTLA-4, B7-1, and B7-2 as the antigen and the well-known structure of antibodies in general.  However, the claims do not recite a general antibody, but an antibody having a specific desired activity. However, Federal Circuit clarification of the law of written description as it applies to antibodies. Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017).

The claims are directed to a genus of anti-PD-1, PDL1, PDL2, CTLA-4, B7-1, and B7-2  antibodies. However, Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. 

Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed anti-PD-1, PDL1, PDL2, CTLA-4, B7-1, and B7-2 antibodies to demonstrate possession.    Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .”  The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e. the antigen.”  The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.

 For instance, citing to Centocor, the Court analogized an antigen and antibody to a lock and a key.  For an antigen where there is only a finite number of binding antibodies, discovering those antibodies may be routine and conventional, and description of the antigen alone may be sufficient.  By contrast, for antigens with millions of keys, or millions of potentially binding antibodies, description of the antigen and even a couple of examples may be far from sufficient.

The disclosed ICB antibodies in the specification are insufficient given the various specificities and epitopes of the genus. 

Finally, the specification fails to discloses a representative number of species falling within the scope of the genus or structural features common to the members of the genus of surgical therapy, chemotherapy, radiation therapy, hormonal therapy, immunotherapy, small molecule therapy, receptor kinase inhibitor therapy, anti-angiogenic therapy, cytokine therapy, cryotherapy or a biological therapy that can treat cancer subject after B-cell exosomes have been detected in a biological sample from the subject.

Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention.  The invention is, for purposes of the written description inquiry, whatever is now claimed.”  (See page 1117.)  The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.”  (See Vas-Cath at page 1116.).  Consequently, Applicant was not in possession of the instant claimed invention.  See University of California v. Eli Lilly and Co. 43 USPQ2d 1398. 

Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed. 

 
7.  Claims 1-4 and  7-20  are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.  

The claims encompass a genus of ICB blockade therapy, a genus of inhibitors of PD-1, PDL1, PDL2, CTLA-3, B7-1 and/or B7-2, a genus of anti-PD-1 monoclonal antibody and/or a genus of anti-CTLA-4 antibody in the treatment of cancer after B-cell exosomes have been detected in a biological sample from the subject.

The specification fails to treat cancer in a subject comprising administering to the subject immune checkpoint blockade (ICB) therapy after B-cell exosomes have been detected in a biological sample from the subject.

Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)).  The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.

Example 1 is directed to analysis of peripheral blood exosomes comprising isolation of exosomes from human plasma, flow cytometry analyses of exosomes and nanoimager analyses.

In Sanofi-Aventisub, the Federal Circuit relied on its prior precedential opinions when determining whether the full scope of a genus was enabled. These decisions included McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091 (Fed. Cir. 2020) (hereafter McRO); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380 (Fed. Cir. 2013) (hereafter Wyeth); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019) (hereafter Enzo); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149 (Fed. Cir. 2019) (hereafter Idenix).

The Federal Circuit, citing McRO, provided guidance on the application of enablement to genus claims, holding that “[a]lthough a specification does not need to describe how to make and use every possible variant of the claimed invention, when a range is claimed, there must be reasonable enablement of the scope of the range.” Sanofi-Aventisub, 987 F.3d at 1085 (internal quotations omitted). Additionally, the Federal Circuit characterized Wyeth as holding “that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality.” Id. at 1086. Similarly, the Federal Circuit characterized Enzo as holding “that the specification failed to teach one of skill in the art whether the many embodiments of the broad claims would exhibit that required functionality.” Id. Finally, the Federal Circuit characterized Idenix as affirming “the district court's determination that the claims had both structural and functional limitations, and that undue experimentation would have been required to synthesize and screen the billions of possible compounds because, given a lack of guidance across that full scope, finding functional compounds would be akin to finding a `needle in a haystack.' ” Id.

This case is akin to the issue in Sanofi-Aventisub, the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement.  While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a `vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure.  In the instant case, the specification discloses some species that performed the claimed function by their names, with the claimed genus of different ICB blockade therapy, inhibitors of PD-1, PDL1, PDL2, CTLA-3, B7-1 and/or B7-2, a genus of anti-PD-1 monoclonal antibody and/or a genus of anti-CTLA-4 antibody. The instant claims are directed to a class of ICB blockade therapy, inhibitors of PD-1, PDL1, PDL2, CTLA-3, B7-1 and/or B7-2, a genus of anti-PD-1 monoclonal antibody and/or a genus of anti-CTLA-4 antibody antibodies that included “a `vast' number of additional antibodies” that the instant specification fails to describe their amino acid sequences.

The scope of the instant claims encompassed a genus of ICB blockade therapy, a genus of inhibitors of PD-1, PDL1, PDL2, CTLA-3, B7-1 and/or B7-2, a genus of anti-PD-1 monoclonal antibody and/or a genus of anti-CTLA-4 antibody and that it was necessary to first generate and then screen each candidate to determine whether it met the functional limitations.  The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.

The claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the two antibodies they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10. 

Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.

In its recent decision in Baxalta Inc. v. Genentech, Inc., No. 2022-1461, 2023 WL 6135930 (Fed. Cir. Sept. 20, 2023) the Federal Circuit found the facts of this case to be “materially indistinguishable from those in Amgen.” Baxalta, 2023 WL 6135930, at *4. According to the Federal Circuit, claim 1 covers “millions of potential candidate antibodies” (id.) that bind to Factor IX/IXa and increase the procoagulant activity of Factor IXa. The court, however, noted that the specification discloses the amino acid sequence of just 11 of those antibodies. And like the roadmap in the patents at issue in Amgen, “the ’590 patent’s roadmap simply directs skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the [11] antibodies they elected to disclose.” (Id.) Missing from the specification, according to the Federal Circuit, was “‘a quality common to every functional embodiment’ ... that would allow a skilled artisan to predict which antibodies will perform the claimed functions” (id.; quoting Amgen Inc. v. Sanofi, 598 U.S. 594, 614 (2023)), such as a common structural or other feature that would allow the antibodies to perform the claimed functions, or an explanation as to why the 11 antibodies do so and others do not. (Baxalta, 2023 WL 6135930, at *4). And the Federal Circuit was not persuaded by Baxalta’s argument that its disclosed hybridoma-and-screening process “predictably and reliably generates new claimed antibodies every time it is performed” (id.), because “it is undisputed that to practice the full scope of the claimed invention, skilled artisans must make candidate antibodies and screen them to determine which ones perform the claimed functions.” (Id.) Also see MPEP 2164.01.

The specification fails to treat cancer in a subject comprising administering to the subject immune checkpoint blockade (ICB) therapy after B-cell exosomes have been detected in a biological sample from the subject.

The instant claims are drawn to a large genus of methods which have not been developed yet to the point where a specific benefit exists in currently available form. 
An abundance of literature shows that the combination of an immune checkpoint inhibitor (e.g., an-anti-PD-1) in combination with another anti-cancer agent does not generally yield desired result.  For example, Dolgin (CANCER DISCOVERY, AACRJournals.org MAY 2023, pages-1033 1023) teach that late-stage trials evaluating the PD-1 inhibitor pembrolizumab in men with prostate cancer have all ended in failure, leading clinicians to conclude that new treatment strategies are needed to help make checkpoint blockade more effective in the immune-suppressed environment of most prostate tumors.  Over and over, trials evaluating PD-1/PD-L1 inhibitors in advanced prostate cancer have missed the mark. The failures have led to questions as to why—and have prompted oncologists to conclude that new treatment strategies are needed.  Two phase III trials of the PD-1 inhibitor pembrolizumab (Keytruda; Merck) were halted earlier this year after interim analyses showed that adding it to the antiandrogen drug enzalutamide (Xtandi; Astellas) and androgen deprivation therapy (ADT) failed to extend survival compared with placebo plus enzalutamide and ADT in men with metastatic castration-resistant prostate cancer (mCRPC; KEYNOTE-641) or metastatic hormone-sensitive disease (KEYNOTE-991).  Trials for mCRPC evaluating pembrolizumab plus docetaxel and pembrolizumab plus the PARP inhibitor olaparib (Lynparza; AstraZeneca)—KEYNOTE-921 and KEYLYNK-010, respectively—had previously come up short as well.  A team co-led by Russell Pachynski, MD, of Washington University School of Medicine in St. Louis, MO, previously showed that nivolumab plus docetaxel has clinical activity in men with chemotherapy-naive mCRPC (Eur J Cancer 2022;160:61–71). But expectations for success are diminishing, especially when factoring in last year's report that another inhibitor of the same pathway—the PD-L1 blocker atezolizumab (Tecentriq; Genentech)—offered no survival benefits over placebo when added to enzalutamide in a phase III mCRPC trial (Nat Med 2022;28:144–53) (see the entire reference).

McGrail et al (Ann Oncol. 2021, 32(5):661-672) teaches hat high tumor mutation burden fails to predict immune checkpoint blockage response across all cancer types. McGrail et al analysis failed to support application of TMB-H as a biomarker for treatment with ICB in all solid cancer types. Further tumor type-specific studies are warranted.

Broderick, JM. (Urology Times, Oct. 30, 2020) teach a strategy of upfront nivolumab (Opdivo) followed by response-dependent sequential use of ipilimumab (Yervoy) did not provide a benefit in patients with advanced renal cell carcinoma (RCC), according to findings from the phase 2 OMNIVORE trial published in the Journal of Clinical Oncology.

Nyberg K., (ILCN, on: January 28, 2021, In: Presidential Symposium, WCLC 2020 Archive ) teach dual PD-1 and CTLA-4 checkpoint blockade confers no therapeutic benefit beyond PD-1 blockade alone in PD-L1–positive NSCLC.

The specification does not provide empirical data to show the efficacy of the ICB blockade therapy on the treatment of cancers such as skin cancer,  basal-cell skin cancer, squamous-cell skin cancer, melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, ketoacanthoma, spindle cell tumors, sebaceous carcinomas, microcystic adnexal carcinoma, Paget's disease of the breast, atypical fibroxanthoma, leiomyosarcoma, or angiosarcoma,  melanoma, metastatic melanoma, Lentigo Maligna, Lentigo Maligna Melanoma, Superficial Spreading Melanoma, Nodular Melanoma, Acral Lentiginous Melanoma, Cutaneous Melanoma, or Desmoplastic Melanoma [0010]).  It is not clear that the skilled artisan could predict the efficacy of the claimed ICB blockade therapy/inhibitors/antibodies on the treatment of cancers encompassed by the claims. It is unpredictable whether treating cancer after B-cell exosomes have been detected in a biological sample from the subject with the anti-MFAP4 antibody, HG-HYB 7-5 would reach a therapeutic end point. It is not clear that the skilled artisan could predict the efficacy of the anti-PD-1, PDL1, PDL2, CTLA-4, B7-1, and/or B7-2 antibody, on the treatment of said cancer. The clinical value of such strategies of the treatment of cancers after B-cell exosomes have been detected in a biological sample from the subject with anti-PD-1, PDL1, PDL2, CTLA-4, B7-1, and/or B7-2 remain to be seen.

The MPEP states that the issue of "correlation" is also dependent on the state of the prior art. In other words, if the art is such that a particular model is recognized as correlating to a specific condition, then it should be accepted as correlating unless the examiner has evidence that the model does not correlate. Even with such evidence, the examiner must weigh the evidence for and against correlation and decide whether one skilled in the art would accept the model as reasonably correlating to the condition. See MPEP 2164.02.

Further, in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297-1303 (CAFC 2005), the court states “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to “inventions” consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the 'inventor' would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis.”

Furthermore, regarding in vivo methods which rely on generally unpredictable mechanisms, ''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 in the art.'' In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction'' refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling (MPEP 2164.03).'' The MPEP also states that physiological activity can be considered inherently unpredictable.

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).

Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.



8.  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.

9.  Claim 40 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mao et al (Cancer Science. 2019;110:2700–2710).

Mao et al teach methods comprising detecting B-cell exosomes in a subject with cancer.  In particular, Mao et al explore the role of circulating exosomes from ESCC in the generation of two main regulatory B (Breg) subsets, including interleukin‐10+ Bregs (B10) and programmed cell death (PD)‐1high Bregs. Firstly, Mao et al observed an elevated percentage of B10 cells in peripheral blood of ESCC patients compared with healthy controls. Then we isolated and characterized exosomes from the peripheral blood of ESCC patients and an ESCC cell line. Exosomes from ESCC patients and the ESCC cell line suppressed the proliferation of B cells and induced the augmentation of B10 and PD‐1high Breg cells (abstract). Mao et al teach the expression of specific exosome markers (CD9 and CD81) on exosomes from the peripheral blood and ECA109 cell line, ESCC patients and healthy controls was validated by western blot analysis (Figure 2A, C, G).

The reference teachings anticipate the claimed invention.

10.  Claim 40 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2019/094692 (IDS).

The `692 publication teaches methods of detecting immune cell-derived protein containing vesicles in a biological sample obtained from a cancer patient (page 5, lines 1-2). Comprising detecting B cell exosomes in a subject with cancer (detecting immune cell-derived protein containing vesicles in a biological sample obtained from a cancer patient (page 5, lines 1-2). The `692 publication  of PD-Ll in melanoma cells by immunofluorescence. PD-Ll co-localized with the exosome marker CD63 (i.e., B-cell-derived exosome marker) (FIG. 1L), and the ESCRT subunit Hrs (FIG. 2C), which mediates the recognition and sorting of exosomal cargos (page 36, lines 22+ and published claims 30-31).

The reference teachings anticipate the claimed invention.
11.  Claims 1-4, 7-21 and 40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Helmink et al (Nature, 577:549-555, 23 January 2020, IDS).

Helmink et al assessed tumor samples histologically to gain insight into the density and distribution of B cells as well as their relationship to tertiary lymphoid structures (TLSs) in patients treated with neoadjuvant ICB (e.g., ipilimumab and nivolumab, Fig. 1-2).  The density of CD20+ B cells and TLSs, and the ratio of TLSs to tumor area were higher in responders than in non-responders in our neoadjuvant melanoma (aka skin cancer) cohort, particularly in early on-treatment samples (P = 0.0008, P = 0.001 and P = 0.002, respectively) (Fig. 2a), which is consistent with previous work that suggested that assessment of early on-treatment immune infiltrate is far more predictive of the response to ICB than assessment of pre-treatment samples.  Helmink et al found increased numbers of B-cell-related exosomes (CD20+) in the peripheral blood of responders compared with non-responders at early on-treatment time points (Extended Data Fig. 2d–j).  Architectural analysis showed that CD20+ B cells were localized in TLSs of tumors of responders, and were colocalized with CD4+, CD8+and FOXP3+ T cells. Helmink et al teach that  previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling that B cell signatures were enriched in the tumors of patients who respond to treatment versus non-responding patients.  Helmink et al demonstrate clonal expansion and unique functional states of B cells in responders. Helmink et al concluded that these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets (abstract and page 551, under B cells localized in the context of TLSs).  Helmink et al provide analysis of peripheral blood exosomes from human plasma using flow cytometric analyses of exosomes, nanoimager analyses and electron microscopy analyses (see Methos and materials, Fig. 2).  

Claims 7-12, 15 are included because Helmink et al assessed the expression of these immune cell gene expression signatures in a pre-surgical ICB trial for patients with metastatic renal cell carcinoma (RCC) (NCT02210117, PD1 blockade monotherapy versus combined CTLA4 (ICB, anti-CTLA4, immunotherapy, anticancer treatment, biological therapy) and PD1 (ICB) blockade versus combined PD1 blockade and bevacizumab (anticancer treatment, anti-angiogenic, immunotherapy, biological therapy)) (Supplementary Table 10) (see page 550, under Similar B cell signature observed in RCC).  Helmink et al teach that the single-cell RNA-seq B cell analysis used a dataset from 32 patients with metastatic melanoma (n = 48 samples) treated with anti-PD1 (n = 37), anti-CTLA4 (n = 2), or anti-PD1 and anti-CTLA4 (n = 9) (page 551, right col., 1st Âś, Fig. 3). Helmink et al teach the combination of Ipi + nivo or nivo (see Fig. 1a-c, Fig.2d).

Claim 13 is included because Helmink et al teaches CD20+ B cells.  Further, Helmink et al assist beads with exosomes stained for flow cytometry analysis for CD63, CD9, CD20, CD27 and GPC1  (see Fig. 2j and sections Flow cytometric analyses of exosomes and Nanoimager analyses).

Claim 14 is included because Fig. 2e show the use of immunocapture assay.

Claims 16-17 are included because Helmink et al teaches at Fig.2d, Schematic for exosomal analyses of serum samples from patients with melanoma on neoadjuvant ICB trial (see also Fig. 2h), peripheral blood (see page 553, under CyTOF shows differential B cell phenotypes).

Claims 16, 18-19 is included because Helmink et al teach analysis of peripheral blood exosomes from human plasma Approximately 1 ml of plasma per patient sample contained in a cryovial was thawed rapidly in a 37 °C water bath. The plasma was transferred into a 1.5-ml Eppendorf tube and centrifuged at room temperature for 5 min at 800g and 10 min at 2,000g. The supernatant was filtered with a 0.22-Οm filter (6789-1302) directly into an ultracentrifuge tube
(Z80615SCA, 331372). The tubes were the ultracentrifuged at 4 °C for 15–16 h at 100,000g using a Beckman Optima XE-90 ultracentrifuge (see section under Analysis of peripheral blood exosomes from human plasma).

The reference teachings anticipate the claimed invention.


12.  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.

13.  Claims 21 and 40 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.

The claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, claims 21 and 40 do not recite something significantly different than a judicial exception. The rationale for this determination is explained below:

The Office has presented “Jan 2019  Federal Register Vol. 84, No. 4” with a two-step analysis for patent subject matter eligibility under 35 USC 101 in view of the case decisions of Supreme Court (Alice Corp Pty.Ltd v. CLS Bank Int’l (2014); Mayo Collaborative Serv. v. Prometheus Labs (2012); Association for Molecular Pathology v. Myriad Genetics Inc. (2013)) and Court of Appeals for the Federal Circuit (University of Utah Research Foundation v. Ambry Genetics Corp. (2014); PerkinElmer Inc. v. Lintema Ltd. (2012)).  

The first step requires that the claimed invention ‘‘must be directed to one of the four statutory categories’’, namely process, machine, manufacture or composition, and the second step requires that the invention ‘‘must not be wholly directed to subject matter encompassing a judicially recognized exception’’, namely a law of nature, a natural phenomenon or an abstract idea (emphasis added).

The instant invention directs to a process of for predicting a response to ICB therapy in a subject by determine the amount of B-cell exosomes, comparing the amount of the B-cell exosomes  and detecting a differential amount of B-cell exosomes in claim 21.  Claim 40 is directed to a process comprising detecting B-cell exosomes in a subject with cancer.

Following the instructions by the guidance, the invention claimed herein satisfies the requirement of the first prong (Step 1) because it directs to a process (method).  

The claims describe a correlation or relationship between the presence of B-cell exosomes in a patient’s sample and the response to ICB therapy in the patient. This limitation sets forth a judicial exception, because this type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo). Additionally, this correlation could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics, or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams). Thus, the claim is directed to at least one exception (Step 2A: YES), which may be termed a law of nature, an abstract idea, or both. 

The present claims do not require performing any steps that are not routine and conventional. For example, the claims do not require using novel reagent to determine the amount of B-cell exosomes, novel monoclonal antibody against CD63. See Ariosa Diagnostics, Inc. v. Sequenom, Inc., F. Supp. 2d, 2013 WL 5863022, at *10 (N.D. Cal. Oct. 30, 2013) noting that "had the inventors of the [patent-in-suit] created an innovative method of performing DNA detection while searching for paternally inherited cffDNA, such as a new method of amplification or fractionation, those claims would be patentable.” Note that this decision was affirmed by the Federal Circuit (No. 2014-1139, -1144. June 2015) wherein it is stated that “Where claims of a method patent are directed to an application that starts and ends with a naturally occurring phenomenon, the patent fails to disclose patent eligible subject matter if the methods themselves are conventional, routine and well understood applications in the art.”

2B. Do the claims as a whole recite something “significantly more” than the judicial exception(s)? No, the claims, as written, are drawn to methods for the predicting a response to ICB therapy or detecting B-cell exosomes in a subject with cancer comprising using a correlation or relationship between the presence of B-cell exosomes in a patient’s sample and prediction of ICB therapy response in the patient. Besides the law of nature, the claim recites additional steps of determining the amount of B-cell exosomes in a sample form a subject to be detected a differential amount of B-cell exosomes compared to a control. . The step is recited at a high level of generality such that it amounts to insignificant presolution activity, e.g., a mere data gathering step necessary to use the correlation. Determining whether B-cell exosomes is present in the biological sample merely instructs a scientist to use any detection technique with any generic reagent/antibody that binds to B-cell exosomes. When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention, and at the time the application was filed, e.g., the routine and conventional techniques of detecting a protein using an antibody to that exosome. Further, it is well established that the mere physical or tangible nature of additional elements such as the obtaining and detecting steps does not automatically confer eligibility on a claim directed to an abstract idea (see, e.g., Alice Corp. v. CLS Bank Int’l, 134 S.Ct. 2347, 2358-59 (2014)).

Moreover, even under further Step 2B: does the claim recite additional elements that amount to significantly more than the judicial exception. The instant steps are well-understood, routine, conventional activity in the field and are not significant more than the judicial exception.
Consideration of the additional elements as a combination also adds no other meaningful limitations to the exception not already present when the elements are considered separately. Unlike the eligible claim in Diehr in which the elements limiting the exception are individually conventional, but taken together act in concert to improve a technical field, the claim here does not invoke any of the considerations that courts have identified as providing significantly more than an exception. Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claim as a whole does not amount to significantly more than the exception itself (Step 2B: NO). The claim is not eligible.

Therefore, the claims recite a correlation which is a law of nature without additional elements that would transform the exception into a patent-eligible application of the exception, are not eligible subject matter under 35 U.S.C. § 101.


14.  No claim is allowed.

15.  Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.

Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.

May 13, 2025

/MAHER M HADDAD/            Primary Examiner, Art Unit 1644                                                                                                                                                                                        



    
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
    


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