DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
The Response to the Election of Species Requirement, filed on October 15, 2025, is acknowledged. Applicant elects with traverse (1) the Staphylococcal enterotoxin species of Staphylococcal enterotoxin B (SEB) and (2) the immune checkpoint molecule PD-1.
Applicant traverses on the grounds that the Examples from the disclosure (e.g., ¶ 0117, 0120) prove that the proposed method of treatment is independent of the selected enterotoxin and that several modulators of different immune checkpoints can be used with the same effect. In particular, Applicant points to experiments illustrating that SEB and SEA “performed equally” with respect to T cell infiltration of tumors. Applicant asserts that both anti-PD-1 and the combination of anti-PD-1/anti-CTLA-4 with SEB reduced tumor size (e.g., Figures 2-3). Applicant states that Figure 4 shows that SEA also allowed T cell infiltration of tumors (Figure 4). Applicant further argues that the SEs will behave in the same way because they are functionally related and share sequence homology (e.g., “70-90%” and “40-60%”).
In response, it is held that the species of Staphylococcal enterotoxins, while being functionally related, each have unique structures despite their sequence homology. These structural differences confer unique differences between the species, which would be recognized by those of ordinary skill in the art. Further, the species of immune checkpoint proteins would likewise be recognized by those of ordinary skill in the art to have unique structures and to be involved in distinct biological processes and pathologies, even if, as a class, inhibitors of immune checkpoint molecules may be used to treat certain cancers. Applicant’s experimental findings do not alter these facts. The Election of Species Requirement remains final.
The claims filed on October 15, 2025 are acknowledged. No claims have been amended, canceled, or newly added. Claims 1-10, 13, and 15 are pending and under examination herein.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See, e.g., page 8, line 20, and page 13, line 25. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 5 is objected to because the listing of immune checkpoint molecules contains redundancies. For example, the pairs of BTLA/CD272 (lines 5 and 6), CD270/HVEM (line 5), and CD137/4-1BB (lines 5 and 6) each refer to alternative names for the same respective immune checkpoint protein. “A2aR” is listed twice, in lines 4 and 6. In addition, “4-IBB” should instead recite “4-1BB” (number one instead of letter I).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3 and 5 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 3, the phrase "preferably" in line 3 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The description of examples or preferences is properly set forth in the specification rather than the claims. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. In the present case, it is unclear whether the claim scope is drawn to one of the members of the closed group of Staphylococcal enterotoxins or specifically to Staphylococcal enterotoxin B.
Regarding claim 5, the phrase "preferably" in lines 6 and 7 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The description of examples or preferences is properly set forth in the specification rather than the claims. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. In the present case, it is unclear whether the claim scope is more narrowly limited to inhibitors (as opposed to “modulators”, which may act as agonists or antagonists) of immune checkpoint proteins, and further, whether the claim scope is more narrowly limited to immune checkpoint inhibitors of LAG-3, CD47, CTLA-4, PD-L1, or PD-1 (as recited in lines 7-9), or more broadly to modulators of one of the immune checkpoint proteins recited in lines 3-6.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 1-6, 8-10, 13, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Terman (US Patent No. 6,126,945; published October 3, 2000) in view of Van Eenennaam (US 2019/0135933 A1) and Rosenberg (The Journal of Immunology (2014) 192(12): 5451-5458).
Terman describes the use of Staphylococcal enterotoxins (A, B, C, D, E) in treatment of cancer as tumoricidal agents (e.g., Abstract). The SEB can be administered “intravenously, subcutaneously, as in adjuvant form, or used extracorporeally in free or bound form to stimulate immunocytes which are subsequently infused into tumor bearing hosts” (col 1). Terman discloses a method of treating a cancer, comprising the step of administering to a patient or subject in need thereof a tumoricidally effective amount of Staphylococcal enterotoxin B or a biologically active fragment thereof (e.g., col 23, 35; claims 1-14), relevant to claims 1, 3-4, and 9. Terman discloses that enterotoxins are heat stable and resistant to trypsin digestion, and that enterotoxins have distinct advantages over previously described Staphylococcal Protein A plasma perfusion systems (e.g., col 2-3).
However, Terman does not expressly teach a combination treatment method further comprising administering an anti-PD-1 antibody, or further administering an anti-PD-1 antibody and one or more further drugs.
Van Eenennaam discloses methods of treating conditions (e.g., solid tumors) ameliorated by stimulation of an immune response via stimulation of CD27 immune cells and/or by inhibition of an immune checkpoint protein such as PD-1, PD-L1, CTLA-4, and others (e.g., Abstract; ¶ 0004, 0080-0087). Van Eenennaam teaches that immune checkpoint inhibitors against the PD-1/PD-L1 pathway and CTLA-4 are in clinical development and have shown promising results in clinical studies (e.g., ¶ 0009). Van Eenennaam teaches that their invention is based on the surprising discovery that the combination of an agonistic anti-CD27 antibody and an immune checkpoint inhibitor results in immune stimulation to an unexpected level (¶ 0014). Van Eenennaam discloses methods that comprise administering the combination of an anti-human CD27 agonist antibody of the invention and an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab) (e.g., ¶ 0014-0021), relevant to claims 1, 5-6, and 10. Van Eenennaam discloses that the combination of an anti-CD27 agonist antibody and anti-PD-1 antibody enhances Staphylococcal enterotoxin B-induced T-cell activation in human PBMCs and in human whole blood compared to either treatment alone (e.g., Figure 1A, Figure 2A, Figure 3).
Relevant to claims 2 and 9, Van Eenennaam discloses that suitable routes of administration for antibodies of the invention include systemic administration (e.g., intramuscular, intravenous, subcutaneous, or intraperitoneal injection) or local administration (injection) directly into the site of action (e.g., ¶ 0099-0100).
Relevant to claim 8, Van Eenennaam discloses a confirmatory experiment in Example 2 wherein human PBMCs isolated from the blood of healthy donors were first combined with antibody treatment (anti-CD27 monotherapy, anti-PD-1 monotherapy, or anti-CD27/anti-PD-1 combination therapy) followed by addition of SEB to effect superantigen-induced IL-2 secretion (¶ 0132-0134; Figure 3).
Rosenberg teaches that IL-2 is a cytokine produced by antigen-stimulated CD4+ T cells, CD8+ cells, and activated dendritic cells (page 5451). IL-2 plays a prominent role in the maintenance of CD4+ regulatory T cells and differentiation of CD4+ T cells into a variety of subsets with different T cells functions. In CD8+ cells, IL-2 stimulates cell growth as well as differentiation into memory and more terminally differentiated lymphocytes (page 5451). Rosenberg describes how early observations that administration of IL-2 promoted durable and curative tumor regression in patients with metastatic melanoma and renal cancer paved the way for later use of IL-2 to grow T cells in vitro that can be used for adoptive cell therapy for cancer, as lymphocytes expanded long-term in IL-2 could retain specific antigen reactivity (e.g., pages 5451-5454). Rosenberg notes that tumors do not express IL-2 receptors and thus the anti-tumor activity of IL-2 administration is the result of IL-2 stimulation of immune cells (page 5453).
In view of the above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a method of treating cancer in a subject having a tumor that comprises administering the combination of SEB (or a biologically active fragment thereof) and an anti-PD-1 antibody. The skilled artisan would have been motivated to do so because Terman teaches that SEB has tumoricidal properties and that enterotoxins have several advantages (e.g., ease of use/administration, safety, efficacy) compared to previously disclosed systems. Further, SEB promotes IL-2 production (as taught by Van Eenennaam), which Rosenburg notes is beneficial in the treatment of cancer since IL-2 stimulates immune cells (with said effect being desired by Van Eenennaam). In addition, Van Eenennaam teaches that immune checkpoint inhibiting antibodies against PD-1, CTLA-4, and CD27 likewise display efficacy in the treatment of solid cancers, and that the combination of an anti-PD-1 antibody with an anti-CD27 antibody enhances SEB-induced IL-2 secretion. There would have been a reasonable expectation of success because, as set forth in MPEP § 2144.06(I), “‘It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.’ In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. Those of ordinary skill in the art would recognize that SEB and anti-PD-1 antibodies are both suitable for the purpose of treating cancer, and their combined use for the same purpose (treating cancer) would not be considered inventive in view of the state of the prior art.
Furthermore, with respect to the schedule of treatment regimens recited in claim 8, there are a finite number of timeframes at which a combination of potential treatments may be administered to a patient, and one of ordinary skill in the art has good reason to pursue known options within his or her technical grasp in order to arrive at an optimal treatment regimen through the process of routine optimization.
With respect to the pharmaceutical composition recited in claim 13, it would be obvious to formulate a pharmaceutical composition comprising the combination of both SEB and an anti-PD-1 antibody, configured for use in the treatment of cancer. One of ordinary skill in the art would recognize that such a formulation could be more conveniently and comfortably administered to a patient by requiring a single administration of drug instead of two separate administration events, and it is within the skill of one of ordinary skill in the art to prepare a pharmaceutical composition comprising more than one therapeutically active ingredient. Furthermore, Terman and Van Eenennaam teach that each of SEB and anti-PD-1 antibodies can be administered intravenously (i.e., in the same manner).
Claims 1 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Terman (US Patent No. 6,126,945; supra) in view of Van Eenennaam (US 2019/0135933 A1; supra) and Rosenberg (The Journal of Immunology (2014) 192(12): 5451-5458; supra) as applied to claims 1-6, 8, and 10 above, and further in view of Bonaventura (Frontiers in Immunology (2019) 10: Article 168; cited in IDS) and Ayers (Journal of Clinical Investigation (2017) 127(8): 2930-2940).
The teachings of Terman are recited in the 35 U.S.C. § 103 rejection above.
However, Terman does not teach treating a tumor characterized by a low IFN-γ response signature, a low BATF3 response signature, and/or a low tumor infiltration signature.
The teachings of Van Eenennaam and Rosenberg are disclosed in the 35 U.S.C. § 103 rejection above.
Bonaventura teaches that while therapeutic antibodies targeting immune checkpoint proteins have been effective for some patients, non-response to treatment is observed in many cases (page 1). Bonaventura teaches that a major factor involved in initial resistance to immune checkpoint protein inhibitors is lack or paucity of tumor T cell infiltration, leading to “non-inflamed” or “cold tumors” (page 1). By contrast, lymphocyte infiltration and IFN-γ status may be key factors for effective anti-PD-1 therapy by defining a “T cell inflamed” phenotype (“hot tumors”) (page 1). Bonaventura teaches that defects in antigen-presenting cells (APCs; which activate T cells) and absence of T cell activation/co-stimulation are among the possible factors that could lead to “cold tumors” (pages 1-3; Figure 1).
Ayers sought to determine whether quantifying a T cell-inflamed microenvironment is a useful pan-tumor determinant of PD-1-directed anti-tumor therapy. Per Ayers, “Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab” (Abstract). Ayers notes, “Elucidation of the underlying immunologic characteristics of the tumor microenvironment associated with response and resistance will improve the identification of patients who will derive the most benefit from anti–PD-1 monotherapy and might reveal additional immunologic determinants that could be targeted in combination with PD-1 checkpoint blockade” (Introduction). Ayers analyzed gene expression profiles (GEPs) using RNA from baseline tumor samples of pembrolizumab-treated patients (e.g., Abstract). Ayers identified several IFN-γ-related genes that are involved in T cell cytolytic activity, antigen presentation, and chemokine production were predictive of PD-1 blockade treatment response across different tumor types, including a preliminary 10-gene signature and an expanded 28-gene gene signature that correlated with the preliminary 10-gene signature (e.g., Results; Figure 1). The “expanded” gene signature described by Ayers includes IL2Rg (which encodes IL2Rγ) (e.g., Table 2). Ayers further noted a general pattern of a lack of objective response in patients whose tumors showed low expression levels across the genes, “assumed to represent tumors without a T cell-inflamed phenotype” (page 2934).
In view of these teachings, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to carry out a combination treatment method based on the collective teachings of Terman, Van Eenennaam, and Rosenberg, in a patient having a tumor with a low interferon-γ response signature. The skilled artisan would have been motivated to do so because, as taught by Ayers and Bonaventura, cancer patients having “cold” tumors are less likely to respond to anti-PD-1 blockade monotherapy, and targeting additional immunological determinants in combination with PD-1 blockade could improve therapeutic response. Increasing T cell costimulation or activation, e.g., by increased IL-2 production via administration of SEB, would be expected to promote a more inflamed or “hot” tumor phenotype and thus increase the likelihood of response to anti-PD-1 blockade. There would have been a reasonable expectation of success because SEB promotes IL-2 production, and IL2Rg (a receptor for IL-2) was among the genes identified by Ayers as having a tight correlation to the preliminary 10-gene IFN-γ gene signature that predicts anti-PD-1 blockade responsiveness.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Chand (Poster P312 presented at SITC Annual Meeting, Washington, DC, November 9-12, 2017) describes the combination of an anti-PD-1 antibody (AGEN2034) with an anti-CTLA-4 antibody, anti-TIGIT antibody, or anti-LAG-3 antibody to enhance T cell responsiveness. Cytokine production (IL-2) induced by AGEN2034 was assessed in PBMCs stimulated with Staphylococcal enterotoxin A (SEA).
Forsberg (US 2010/0111978 A1) discloses compositions comprising a conjugate of a bacterial superantigen (e.g., Staphylococcal enterotoxin) and an antibody moiety, and uses thereof in treating cancer.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:00am - 5:30pm EST.
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) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643