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 .
DETAILED ACTION
1. Claims 37-40, 42, 45, 46, 48-52, 56-59, 64, 65, 67-71 and 73 are currently pending.
Election/Restrictions
2. Applicant’s election without traverse of Group I, claims 37-40, 42, 45, 46, 48-52, 56-59, 64, 65, and 67-71 in the reply filed on March 2, 2026 is acknowledged.
Claim 73 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 2, 2026.
Claims 37-40, 42, 45, 46, 48-52, 56-59, 64, 65, and 67-71 are currently under examination.
Information Disclosure Statement
3. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
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.
4. Claims 37-40, 42, 45, 46, 48-52, 56-59, 64, 65, and 67-71 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
To fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must 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 fully describe the method as claimed.
Independent claim 37 is drawn to a method of improving the efficacy of a superantigen conjugate comprising a superantigen covalently linked to a targeting moiety that binds a cancer antigen in treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a B-cell depleting agent prior to administering the superantigen conjugate to the subject.
Independent claim 38 is drawn to a method of promoting infiltration if T-cells and/or reducing infiltration of regulatory T-cells (Tregs) into a tumor in a subject in need thereof, the method comprising administering to the subject: (i) an effective amount of a B-cell depleting agent; and then (ii) an effective amount of a superantigen conjugate comprising a superantigen covalently linked to a targeting moiety that binds a cancer antigen expressed by cancerous cells of the tumor, thereby to promote infiltration of T-cells and/or reduce infiltration of Tregs into the tumor.
Independent claim 42 is drawn to a method of treating cancer in a subject in need thereof, the method comprising administering to the subject: (i) an effective amount of a B-cell depleting agent; and then (ii) an effective amount of a superantigen conjugate comprising a superantigen covalently linked to a targeting moiety that binds a cancer antigen expressed by cancerous cells of the tumor.
The examples describe in vivo studies testing a tumor targeted superantigen in combination with anti-CD20 antibody in a model with colon cancer. The examples also describe the effect of a colon tumor targeted superantigen in combination with anti-CD20 antibody on CD8+ expansion and infiltration. However, the breadth of the claims has not been fully described by the specification. The method as claimed does not describe the parameters necessary for improving the efficacy of a superantigen conjugate. How does one know that the efficacy of a superantigen has occurred simply by administering to the subject an effective amount of any B-cell depleting agent prior to administering any superantigen conjugate to the subject? Additionally, will these methods work with tumors or cancer cells beyond the demonstrated colon cancer model?
In the instant case, to fulfill the written description requirement, the missing components must be adequately described. As it pertains to, for example, cancer, which is one of several broadly claimed diseases/conditions (genus), it is noted that cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. Types of cancer include, but certainly are not limited to: CNS cancers which cover a very diverse range of cancers in many categories and subcategories. They include an immense range of neuroepithelial tumors, which include gliomas, the most common subtype of primary brain tumors. Other neuroepithelial tumors include astrocytic tumors (e.g. astrocytomas) oligodendroglial tumors, ependymal cell tumors (e.g. myxopapillary ependymoma), mixed gliomas (e.g. mixed oligoastrocytoma and ependyma-astrocytomas) tumors of the choroid plexus(choroid plexus papilloma, choroid plexus carcinoma), assorted neuronal and neuroblastic tumors (e.g. gangliocytoma, central neurocytoma, dysembryoplastic neuroepithelial tumor, esthesioneuroblastoma, olfactory neuroblastoma, olfactory neuroepithelioma, and neuroblastomas of the adrenal gland), pineal parenchyma tumors (e.g. pineocytoma, pineoblastoma, and pineal parenchymal tumor of intermediate differentiation), embryonal tumors (e.g. medulloepithelioma, neuroblastoma, ependymoblastoma, atypical teratoid/rhabdoid tumor, desmoplastic medulloblastoma, large cell medulloblastoma, medullomyoblastoma, and melanotic medulloblastoma) and others such as polar spongioblastoma and gliomatosis cerebri. There are vascular brain Tumors e.g. the hemangioblastomas, there is CNS Lymphoma (which can be primary or secondary) and Meningeal Carcinomatosis. There are lymphoma and haemopoietic neoplasms including malignant lymphomas (which can be primary or secondary), plasmacytoma, and granulocytic sarcoma. And there are many, many others.
The state of art recognizes that there never has been a compound capable of treating cancers generally. “The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally. In re Application of Hozumi et al., 226 USPQ 353 states: “In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way”. There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers.
The attempts to find compounds to treat the various cancers arguably constitute the single most massive enterprise in all of pharmacology. This has not resulted in finding any treatment for tumors generally. Indeed, the existence of such a "silver bullet" is contrary to our present understanding in oncology. This is because it is now understood that there is no “master switch” for cancers generally; cancers arise from a bewildering variety of differing mechanisms. Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, primarily a wide variety of failures of the body's cell growth regulatory mechanisms, but also such external factors such as viruses (an estimated at least 20% are of viral origin e.g. Human papillomavirus, EBV, Hepatitis B and C, HHV-8, HTLV-1 and other retroviruses, and quite possibly Merkel cell polyomavirus, and there is some evidence that CMV is a causative agent in glioblastoma), exposure to chemicals such as tobacco tars, excess alcohol consumption (which causes hepatic cirrhosis, an important cause of HCC), ionizing radiation, and unknown environment factors.
Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. The skill thus depends on the particular cancer involved. Given the fact that, historically, the development of new cancerous drugs has been difficult and time consuming the quantity of experimentation needed is expected to be great.
The written description requirement may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 claimed invention.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
Written description requirement 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. The Guidelines further state, "[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus" (Id. at 1106); accordingly, it follows that an adequate written description of a genus cannot be achieved in the absence of a disclosure of at least one species within the genus.
Therefore, absent a detailed and particular description the skilled artisan could not immediately recognize or distinguish members of the claimed method. Therefore, because the art is unpredictable, in accordance with the Guidelines, the description do not meet the written description requirements.
Claim Rejections - 35 USC § 112
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.
5. Claim 37 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 37 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: the steps necessary to know a degree of efficacy improvement. Which steps are necessary to determine that the efficacy of said superantigen has been improved?
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
6. Claim(s) 37-40, 42, 45, 46, 48-52, 56-59, 64, 65, and 67-71 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nathan et al., US 10,314,910; Published: 6/11/19.
Independent claim 37 is drawn to a method of improving the efficacy of a superantigen conjugate comprising a superantigen covalently linked to a targeting moiety that binds a cancer antigen in treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a B-cell depleting agent prior to administering the superantigen conjugate to the subject.
Independent claim 38 is drawn to a method of promoting infiltration if T-cells and/or reducing infiltration of regulatory T-cells (Tregs) into a tumor in a subject in need thereof, the method comprising administering to the subject: (i) an effective amount of a B-cell depleting agent; and then (ii) an effective amount of a superantigen conjugate comprising a superantigen covalently linked to a targeting moiety that binds a cancer antigen expressed by cancerous cells of the tumor, thereby to promote infiltration of T-cells and/or reduce infiltration of Tregs into the tumor.
Independent claim 42 is drawn to a method of treating cancer in a subject in need thereof, the method comprising administering to the subject: (i) an effective amount of a B-cell depleting agent; and then (ii) an effective amount of a superantigen conjugate comprising a superantigen covalently linked to a targeting moiety that binds a cancer antigen expressed by cancerous cells of the tumor.
Nathan discloses methods for enhancing the potency of a targeted cancer immunotherapy in a subject by using a superantigen in combination with an immunopotentiator. The invention is based, in part, upon the discovery that a targeted immune response against a cancer in a subject can be significantly enhanced by combining a superantigen-based therapy with an immunopotentiator that can (a) stimulate activating T-cell signaling, (b) repress T-cell inhibitory signaling between the cancerous cells and a T-cell, (c) repress inhibitory signaling that leads to T-cell expansion, activation and/or activity via a human IgG4 immunoglobulin-mediated pathway, or (d) a combination of two or more of the foregoing (see column 2, lines 31-40).
In one aspect, the invention provides a method of treating a cancer in a subject in need thereof. The method comprises administering to the subject (i) an effective amount of a superantigen conjugate, the conjugate comprising a superantigen covalently linked to a targeting moiety that binds a first antigen preferentially expressed by cancerous cells within the subject, and (ii) an effective amount of an immunopotentiator (for example, a checkpoint pathway inhibitor) effective to at least one or more of (a) stimulating activating T-cell signaling, (b) repressing T-cell inhibitory signaling between the cancerous cells and a T-cell, and/or (c) repressing inhibitory signaling that leads to T-cell expansion, activation and/or activity via human IgG4 immunoglobulin-mediated pathway (i.e., via a non-human IgG1-mediated immune response pathway), thereby to potentiate an immune response in the subject against the cancerous cells to treat the cancer. Superantigen-based therapies may upregulate the secretion of interferon γ from T-cells, which in turn may upregulate PD-L1 expression. Superantigen conjugate-based therapies effect response rates of PD1 inhibitors (see column 2, lines 41-65; meets claims 64-65).
Furthermore, the superantigen conjugate and the immunopotentiator may be co-administered together or sequentially with one or more additional agents that enhance the potency and/or selectively of the therapeutic effect. Such agents include, for example, corticosteroids, additional immune modulators, and those compounds designed to reduce the patient's possible immunoreactivity to the administered superantigen conjugate. For example, immunoreactivity to the administered superantigen may be reduced via co-administration with, for example, an anti-CD20 antibody and/or an anti-CD19 antibody (see column 3, lines 1-13; meets claims 37, 38, 42). In certain embodiments, the superantigen present in the superantigen conjugate binds to a T-cell receptor on a surface of a T-cell, for example, a CD4+ and/or a CD8+ T-cell (see column 3, lines 14-17).
The targeting moiety can be used to target the conjugate to the cancerous cells by preferentially binding one or more different antigens, for example, one or more cell surface antigens, expressed by the cancerous cells. In certain embodiments, the cell surface antigen is, for example, a 5T4 oncofetal cancer antigen, which is present on cancer cells as well as certain cancer stem cells. Although a variety of targeting moieties can be used to target the superantigen to the cancerous cells expressing the first antigen, in certain embodiments, the targeting moiety is an antibody, for example, an anti-5T4 antibody. In certain embodiments, the targeting moiety is a Fab fragment that binds 5T4 (see column 3, lines 24-36; meets claims 50-51).
Moreover, in certain embodiments, the immunopotentiator is a checkpoint pathway inhibitor. For example, in certain embodiments, the immunopotentiator reduces expression of, or activity of, a Programmed Cell Death-Ligand (PD-L), for example, PD-L1 or PD-L2, expressed on the surface of the cancerous cells. PD-L is a ligand that binds to a Programmed Cell Death-1 receptor (PD-1), which is expressed on T-cells. Certain cancer cells express PD-L to reduce the activation or activity of T-cells via a PD-1 checkpoint pathway so as to evade the subject's immune system. In certain embodiments, the immunopotentiator is an anti-PD-1 antibody that prevents PD-L, for example, PD-L1 or PD-L2, from binding to PD-1 expressed on the surface of the T-cell. In certain embodiments, the anti-PD-1 antibody has or is based on a human IgG4 immunoglobulin isotype that induces much lower antibody-dependent cell-mediated toxicity (ADCC) than a human IgG1 immunoglobulin isotype (see column 3, lines 42-58; meets claims 64-65).
In certain embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab and pembrolizumab. Other PD-1 inhibitors include (i) anti-PD-1 antibodies, for example, MK-3475 (Merck & Co), pidlizumab (CureTech), AMP-224 (AstraZeneca/Medimmune) and AMP-514 (AstraZeneca/Medimmune), and (ii) anti-PD-L1 antibodies, for example, MPDL3280A (equivalent to atezolizumab) (see column 3, lines 51-67; meets claims 67-70).
Further, it is understood that the method can be used to treat a variety of cancers, for example, a cancer selected from the group consisting of breast cancer, cervical cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, and skin cancer (see column 4, lines 12-18; meets claim 42).
In order to increase specificity, the superantigen preferably is conjugated to a targeting moiety to create a targeted superantigen conjugate that binds an antigen preferentially expressed by a cancer cell, for example, a cell surface antigen such as 5T4. The targeted superantigen conjugate should retain the ability to activate large numbers of T lymphocytes.
Only with the superantigen/immunopotentiator therapy of the instant invention is such a distinct time frame for activity plausible, thereby allowing the novel integrated high dose cytostatic agent/immunotherapy treatment (see column 33, lines 41-45; meets claim 71).
Nathan discloses a superantigen comprising the amino acid sequence of SEQ ID NO: 3, as well as an anti-5T4 antibody comprising a heavy chain comprising amino acid residues 1-222 of SEQ ID NO: 8, SEQ ID NO: 8 and 9, which encompasses amino acid residues 1-214. See SCV results attached below; meets claims 49, 56 and 57).
SEQ ID NO: 3
PNG
media_image1.png
237
442
media_image1.png
Greyscale
PNG
media_image2.png
304
465
media_image2.png
Greyscale
SEQ ID NO: 9
PNG
media_image3.png
303
465
media_image3.png
Greyscale
SEQ ID NO: 8 residues 1-222
PNG
media_image4.png
307
475
media_image4.png
Greyscale
As it pertains to claims 37 and 38, Nathan discloses the same method steps as the currently claimed. Said method must necessarily improve the efficacy of a superantigen conjugate, promote infiltration of T-cells or reduce infiltration of Tregs into a tumor, absent evidence to the contrary.
Conclusion
7. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Forsberg et al., WO 03/002143 A1; superantigen; 100% sequence identity to SEQ ID NO: 3, 9, 8Fus9 and 1-122 of SEQ ID NO: 8
8. No claim is allowed.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAKIA J JACKSON-TONGUE whose telephone number is (571)272-2921. The examiner can normally be reached Monday-Friday 930AM-530PM.
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, Anne Gussow can be reached at (571) 272-6047. 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.
/LAKIA J JACKSON-TONGUE/Examiner, Art Unit 1645 April 17, 2026
/BRIAN GANGLE/Primary Examiner, Art Unit 1645
Prosecution Insights