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
Status
Claims 1-13 are pending and presented for examination.
Priority
This application is a Continuation of U.S. Application No. 17/393,587 filed August 4, 2021, which claims priority to and benefits based on U.S. Provisional Patent application No. 63/060,779 filed August 4, 2020.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 10/31/2023 and 5/9/2025 has/have been considered by the Examiner. The submission(s) is/are in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered.
Claim Objections
In Claims 1-4, the term “or” has been inserted between the final two compound structures in each list to present the compounds in the alternative.
Claim Rejections - 35 USC § 112 - Indefiniteness
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 1-13 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.
In Claims 1 and 12:
The claims define variable R11; however, R11 does not appear in the chemical structure. It is therefore unclear what role, if any, R11 has in defining the claimed compound. Applicant is required to clarify the claims by deleting the extraneous definitions or by identifying the location of R11 in the recited claims.
The remaining claims are rejected for depending on a rejected claim and not resolving the aforementioned ambiguity.
Claim Rejections - 35 USC § 112 – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3 and 5-13 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.
The written description requirement is distinct from the enablement requirement; this was first pointed out by the court in In re Ruschig, 379 F.2d 990, 154 USPQ 118 (CCPA 1967), and clarified in Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 19 USPQ2d 1111 (Fed. Cir. 1991). The issue of whether the claimed subject matter is adequately supported/described by the specification is a question of fact. Id. at 1563, 19 USPQ2d at 1116.
When considering whether the claimed subject matter complies with the written description requirement, Applicants' disclosure should be read in light of the knowledge possessed by those skilled in the art.
"[T]he disclosure in question must be read in light of the knowledge possessed by those skilled in the art, and that knowledge can be established by affidavits of fact composed by an expert, and by referencing to patents and publications available to the public..."
In re Lange, 644 F.2d 856, 863, 209 USPQ 288, 294 (CCPA 1981). See also, In re Alton, 76 F.3d 1168, 37 USPQ2d 1578 (Fed. Cir. 1996).
Applicants enjoy the presumption that their patent application is valid and all statements contained therein are accurate; it is the PTO's burden to demonstrate why any of Applicants claims should be rejected or why any of Applicant's statements should be doubted.
it is incumbent upon the Patent Office, whenever a rejection.., is made, to explain why it doubts the truth or accuracy of any statement in a supporting disclosure and to back up assertions of its own with acceptable evidence or reasoning which is inconsistent with the contested statement. Otherwise, there would be no need for the applicant to go to the trouble and expense of supporting his presumptively accurate disclosure.
In re Marzocchi, 439 F.2d 220, 224, 169 USPQ 367, 370 (CCPA 1971). The court has made it clear that such challenges apply to written description rejections:
"we are of the opinion that the PTO has the initial burden of presenting evidence or reasons why persons skilled in the art would not recognize in the disclosure a description of the invention defined by the claims."
In re Wertheim, 191 USPQ 90, 97 (CCPA 1976).
If successful in presenting such evidence and argument, the burden then shifts to the Applicant to provide evidence that would convince one to the contrary that the disclosure as a whole provides written description support for the claimed subject matter.
Claimed Invention
Applicant's claimed invention is directed to treating cytokine release syndrome using compounds of the structure
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Chemical Formula 6 as defined further by the claims.
One of ordinary skill in the art would not recognize that Applicants had possession of the broad generic invention at the time the invention was made. The invention requires varying substituent modifications that read on millions of different compounds. Applicant alleges that any compound encompassed by these structures is useful for inhibiting estrogen-related receptors gamma (ERRɣ), treat any cytokine release syndrome (CRS) that’s caused by an infection including bacterial or viral or caused by inflammation including sepsis or pneumonia. The specification recognizes that binding is an important factor in the structure and thus activity of the compounds (US PG-PUB 2024/0082240 A1, Specification ¶¶ 5, 23). However, effective binding of drug molecules to receptors involves multiple complex factors. One of the factors involves the functional groups of receptor pockets interacting with specific regions of the drug/ligand in a "lock and keys" fashion (Dick RM (2011). "Chapter 2. Pharmacodynamics: The Study of Drug Action". In Ouellette R, Joyce JA. Pharmacology for Nurse Anesthesiology. Jones & Bartlett Learning:pp. 17-26 - particularly p. 17, fight column, second paragraph; Figure 2-1 at p. 18; p. 18, right column second paragraph). For example, a positively charged group at a specific location within the binding pocket may interact with a negatively charged region on a ligand, thus increasing the binding force between the two compounds and increasing the affinity. Another important factor is the effect the drug has when it interacts with a receptor or the intrinsic activity (Dick, p. 18, right column, 3rd paragraph). It is known that "seemingly minor modifications of the molecule may result in a profound change in pharmacological response (increase, diminish, completely destroy, or alter the nature of the response). In pursuing analog design and synthesis, it must be recognized that the newly created analogs are different chemical entities from the lead compound. It is not possible to retain all and exactly the same solubility and solvent partition characteristics, chemical reactivity and stability, acid or base strength, and/or in vivo metabolism properties of the lead compound. Thus, although the new analog may demonstrate pharmacological similarity to the lead compound, it is not likely to be identical to, nor will its similarities and differences always be predictable." J. G. Cannon Chapter Nineteen in Burger's Medicinal Chemistry and Drug Discovery, Fifth Edition, Volume I: Principles and Practice, Wiley-Interscience 1995, pp. 783-802, 784.
The written description does not provide support for the various species of the claimed invention and one of ordinary skill in the art would not accept that Applicant was in possession of the claimed invention at the time the application was filed. Applicant has claimed the compounds built around the key molecule of
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Applicant has further defined the substituent modifications that give rise to varying species within the generally claimed genus. Applicant has only demonstrated possession of the compounds defined in the US PG-PUB 2024/0082240 A1, Specification ¶ 0070.
Applicant claims functionalities that are not functional equivalents without the synthetic support to lead a skilled artisan that one would readily be in possession of those species based on the support of the instant disclosure. For example, Applicant claims that the Ar group can be any structure encompassed by (C6-C12)aryl and may be substituted with any one of moieties that are structurally divergent (e.g., hydroxy, alkoxy, nitro, alkylsulfonylamino, guanidino, etc.). Each potential substituent may be combined with any one of potential moieties for variables R31 and R32 (e.g., independently alkyl, amidino, alkoxycarbonyl, cycloalkyl, etc.); however, the embodiments exemplified are relatively very limited in number of described moieties and are not representative of the multitude of moieties encompassed by the claims. The problem with the lack of written description is exacerbated by the limited nonrepresentative numbers described for the following variables: R1 and R2.
While the specification demonstrates possession of a plurality of species as defined at ¶ 0070 of US PG-PUB 2024/0082240 A1, Applicant claims a broad plurality of species that one skilled in the art would not accept is in Applicant’s possession. Accordingly, Claims 1-13 do not have written description support.
Claim Rejections - 35 USC § 112 –Scope of Enablement
Claims 1-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for managing lipopolysaccharide (LPS)-induced cytokine release syndrome by administering Compound 18a (i.e., DMRC200344 – compound of instant Claim 12), does not reasonably provide enablement for 1) managing LPS-induced cytokine release syndrome with any other compound of Chemical formula 6 other than Compound 18a or 2) managing any cytokine release syndrome that is not induced by LPS with any compound of Chemical formula 6 including Compound 18a. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement requires a determination of whether the disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention. That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, breadth of claim, state and predictability of the art:
The nature of the invention is the use of compounds encompassed by
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Chemical Formula 6 (as further defined in the claims) for treating/managing any cytokine release syndrome (CRS). The compounds were recognized in the prior art as estrogen-related receptor gamma (ERRg) inhibitors. Here, the instant specification advances the proposal that the compounds effectively treat cytokine release syndrome. However, the claims read on an invention that is much broader than what the written description provides enabling support for. The claims are so broad as to encompass the therapeutic use of millions of distinct compounds for treating cytokine release syndrome no matter the cause of the syndrome. However, neither the prior art nor the instant specification establishes predictability that a drug that inhibits ERRg would also inhibit cytokine release syndrome. Cytokine release syndrome (CRS) is a systemic inflammatory response that can be triggered by a variety of factors such as infections and certain drugs. The term “cytokine release syndrome” was first coined in the early ‘90s, when the anti-T-cell antibody muromonab-CD3 (OKT3) was introduced into the clinic as an immunosuppressive treatment for solid organ transplantation. See Shimabukuro-Vornhagen et al. (“Cytokine release syndrome.” J Immunother Cancer. 2018 Jun 15;6(1):56. doi:10.1186/s40425-018-0343-9. PMID: 29907163; PMCID: PMC6003181 – 10/31/2023 IDS.) CRS can be a result of multiple types of sources but there is no evidence in the prior art or in the instant specification that ERRg is involved in CRS pathology. For example, CRS has been described after infusion of several antibody-based therapies such as anti-thymocyte globulin (ATG), the CD28 superagonist TGN1412, rituximab, obinutuzumab, alemtuzumab, brentuximab, dacetuzumab, and nivolumab. Additionally, CRS was reported in the setting of haploidentical donor stem cell transplantation, and graft-versus-host disease. Cytokine storm due to massive T cell stimulation is also a proposed pathomechanism of severe viral infections such as influenza. T cell-engaging immunotherapies include bispecific antibody constructs and chimeric antigen receptor (CAR) T cell therapies. See p. 1, right column. Given that several differential diagnoses have a clinical presentation that is very similar to CRS, making a definitive diagnosis of CRS is very challenging. Since some of the therapies given for conditions other than CRS can actually mitigate the effectiveness of immunotherapy, the development of reliable diagnostic test that help to make the diagnosis of CRS are a high priority for future research. See p. 7, left column. The pathophysiology of CRS is only incompletely understood. CRS is usually due to on-target effects induced by binding of the bispecific antibody or CAR T cell receptor to its antigen and subsequent activation of bystander immune cells and non-immune cells, such as endothelial cells. See p. 7, left column. CRS can be induced by direct target cell lysis with consecutive release of cytokines like interferon gamma (IFN-γ) or tumor necrosis factor alpha (TNF-α) or by activation of T cells due to therapeutic stimuli with subsequent cytokine release. These cytokines trigger a chain reaction due to the activation of innate immune cells like macrophages and endothelial cells with further cytokine release. See Fig. 2; see also Fig. 3.
The management of the toxicities of cancer immunotherapy is challenging clinical problem. Since T cell-engaging therapies are a relatively recent development there are still many unanswered questions regarding the optimal clinical management of CRS. See p. 9, right column. The recommendations for the management of CRS are thus still evolving constantly. Current treatment algorithms for CRS are based on expert opinion and represent the experience of the pioneers in the field of T cell-engaging immunotherapies. The most widely used grading scheme for the severity of CRS was developed by the National Cancer Institute (NCI). See Fig. 3.
Even though there are many commonalities regarding the clinical presentation and pathophysiology of CRS in patients receiving bispecific T-cell engaging (BiTE) or CAR T cells, there are also important differences. The most important difference between BiTE and CAR T cells is that BiTE can be given repeatedly while CAR T cells are usually manufactured in limited amounts and thus are only administered once. The current approaches to prevention and treatment of CRS in patients receiving these two types of T cell engaging therapies therefore differ substantially.
Thus, CRS can be caused by multiple distinct factors including multiple different compounds, antibodies and cell therapies. The pathophysiology of CRS is not well understood but it is known that different causes of CRS can have very different therapies and one has to be careful with differential diagnosis because therapy that is effective for similar clinical presentation can actually mitigate treatment of CRS.
2. The amount of direction or guidance provided and the presence or absence of working examples:
The specification fails to provide adequate guidance to treat CRS, generally, using any of the compounds of
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Chemical Formula 6. However, the specification does provide working example of a single compound, Compound 18a, at p. 36 that demonstrates it can be used to inhibit endotoxemia (LPS in the blood stream). No other compound was shown to be effective for inhibiting endotoxemia besides Compound 18a. The specification does not provide any working examples showing effectiveness in treatment of CRS.
3. The relative skill in the art and quantity of experimentation necessary:
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used to ameliorate CRS despite its cause. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success. Although, one of ordinary skill in the art is one with access to reagents, tools and equipment used for diagnosing disease, performing tests and/or administering treatment to individuals. The skilled artisan also has many years of training and experience in either the clinical or laboratory environment or both. Therefore, it is clear that the level of skill of one in the art is high. However, this high level of skill is overcome in view of the limited teachings provided by the specification and the unpredictable state of the art, it would require the skilled artisan undue experimentation to make and use the invention commensurate to the scope of the claims.
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.
Claims 1-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hwang et al. (US PG-PUB 2019/0167820 A1 – 5/9/2025 IDS).
Claimed invention
The claims are drawn to preventing or treating, preventing or managing cytokine release syndrome (CRS) in a subject by administering a compound of
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Chemical Formula 6 such as Compound 18a
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Claim interpretation
The claims are drawn to embodiments wherein CRS is treated and prevented from occurring in a subject wherein the subject is not even afflicted with a CRS at all. Thus, if the compound of
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Chemical Formula 6 is administered for any reason, then the claimed method of preventing CRS is anticipated. Furthermore, because the term “treating” is defined as encompassing preventing, then methods of treating CRS is also anticipated by a reference that merely teaches the administration of a compound of
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Chemical Formula 6 for any reason.
Prior art
Hwang exemplifies in vivo administration of compound 18a
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. See 0295. Therefore, Hwang anticipates the claimed invention because compound 18a is encompassed by Chemical formula 6.
Claims 2-4 are drawn to narrowing embodiments of compounds of
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Chemical Formula 6. Compound 18a meets each of these compounds.
Claims 5-9 are drawn to different types of CRSs and different causes thereof. Because the claims are drawn to preventing these CRSs, the in vivo administration of compound 18a by Hwang would prevent CRS as claimed.
Claims 10-11 are drawn to intended results that occur after the compound is administered to the subject. However, these intended results do not give further meaning and purpose to the manipulative steps of administering the therapeutic agent for the treatment of the patient. Therefore, the intended results are not given patentable weight because they simply express the intended result of the process steps positively recited. See MPEP § 2111.04.
Independent Claim 12 is drawn to diminishing supraphysiological levels of one or more selected from INFb, IL1b, TNFα and IL6 in a subject in need thereof by administering a compound of Chemical Formula 6. The mere in vivo administration of Compound 18a would inherently diminish supraphysiological levels of one or more selected from INFb, IL1b, TNFα and IL6 because this feature is an inherent property of compounds of Chemical Formula 6.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,850,246. Although the claims at issue are not identical, they are not patentably distinct from each other because each claim set is drawn to a method for treating or managing CRS in a subject by administering the same compounds – those claimed being species of current Chemical formula 6.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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