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 .
Priority
This application is a national stage application under 35 U.S.C. § 371 of
International Application No. PCT/SE2022/050570, filed 06/10/2022, which claims the priority benefit of SWEDEN Application No. 2150825-4, filed 06/28/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/22/2023, and 04/15/2025 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of the Application
Claims 22-41 are pending in the application and currently under examination.
Claim Interpretation
Claim limitations regarding conditions or diseases mediated by mast cells are being interpreted as including cancer. “In some aspects, the present invention relates to alleviation, prevention and/or treatment of a condition or disease, wherein said condition or disease is mediated by mast cells. Mast cells are known to mediate a number of diseases, including mastocytosis, mast cell activation syndrome, type I hypersensitivity, cardiovascular disorders, hereditary alpha tryptasemia, and cancer.” (specification, pg. 10, lines 10-14).
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.
Claims 22-41 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 a method of treating cancer, does not reasonably provide enablement for prevention of said disease or disorder. 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.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In In re Wands, 8 USPQ2d 1400 (1988), the factors to be considered in determining whether a disclosure meets the enablement requirement are as follows:
1. The nature of the invention
2. The state of the prior art
3. The predictability or lack thereof in the art
4. The amount of direction or guidance present
5. The presence or absence of working examples
6. The breadth of the claims
7. The quantity of experimentation needed, and
8. The level of skill in the art
The Nature of the Invention and Breadth of the Claims
Claim 22 is drawn to a method for alleviating, preventing and/or treating a condition or disease mediated by granulocytes comprising acidic cytoplasmic granules comprising administering monensin to the subject.
The State of the Prior Art and the Predictability or lack thereof in the art
“monensin is a highly potent compound for inducing selective apoptosis in granulocytes comprising acidic C)1oplasmic granules. Eosinophils and mast cells are examples of such granulocytes.
Hence, it is a first object to provide monensin for use in the alleviation, prevention and/or treatment of a condition or a disease, wherein said condition or disease is selected from conditions and diseases mediated by granulocytes comprising acidic cytoplasmic granules” (specification p. 3, lines 9-14). “Further, it is demonstrated that monensin effectively reduces the number of granulocytes comprising acidic cytoplasmic granules. It ,vas found that monensin selectively induces cell death in said granulocytes. The cell death was further demonstrated to be apoptosis. The apoptosis may be caspase independent apoptosis. Monensin selectively induces apoptosis in granulocytes comprising acidic cytoplasmic granules, and the effect is more pronounced in mature granulocytes.” (specification, pg. 3, lines 22-25 through pg. 4, line 2)
The Amount of Guidance Present and Presence/Absence of Working Examples
The only guidance disclosed by the specification regarding preventing a condition or disease mediated by granulocytes comprising acidic cytoplasmic granules is found on page 8:
“In some aspects, the present invention relates to alleviation, prevention and/or treatment of a condition or disease, wherein said condition or disease is mediated by mast cells.
Mast cells are known to mediate a number of diseases, including mastocytosis, mast cell
activation syndrome, type I hypersensitivity, cardiovascular disorders, hereditary alphatryptasemia, and cancer.”
The specification does not provide any guidance for determining which particular patient population would be susceptible to developing condition or disease mediated by granulocytes comprising acidic cytoplasmic granules. Also lacking are data showing that the compounds are capable of treating all or every condition or disease mediated by granulocytes comprising acidic cytoplasmic granules. The disclosures in the specification of a combination treatment in which monensin is administered in combination with one or more other anti-eosinophil cell drugs disclose they may provide a more efficient therapy to a subject in need thereof and indicates solely that the compounds can treat the claimed diseases/disorders dependent on granulocytes, not prevent them.
The quantity of experimentation needed, and level of skill in the art
In order to treat every or all conditions or diseases mediated by granulocytes types, one would need to precisely identify those subjects with the disease or disorder who are likely to respond to treatment, administer the claimed invention, and demonstrate that administration directly resulted in the subject overcoming the disease or disorder. One skilled in the art would conclude that the guidance in the specification would not have taught one skilled in the art how to treat every or all types of conditions or diseases mediated by granulocytes using the compound of monensin, because there is no guidance for how to select a patient population and no evidence that the claimed compound can broadly treat every type of condition or disease mediated by granulocytes. Given the lack of guidance in the specification and the lack of success in the prior art, one skilled in the art would find that preventing the claimed diseases or disorders would require experimentation that is unduly burdensome. This rejection may be overcome by cancelling claim 22, or amending the claim language by removing the term “prevention” from the claim.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 22-25, 27-28 and 39 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Gullberg (Processing of Human Cathepsin G after Transfection to the Rat Basophilic/Mast Cell Tumor Line RBL).
Gullberg teaches azurophil granules of neutrophil granulocytes contain neutral proteases such as cathepsin G and further discloses rat basophilic/mast cell tumor line RBL-1 and that the compound monensin inhibits processing and enzymatic activation of human cathepsin G transfected to rat RBL-1 cells, is proteolytically processed into enzymatically active forms and that subcellular transfer to granular organelles occurs. As the processing of transgenic human cathepsin G corresponds to that of endogenous protease of myeloid cells, the model should provide new unique possibilities to further characterize the activation and granular targeting of myeloid serine proteases. (Abstract, pg. 25219, 1st para) The teachings of Gullberg anticipate the instant claims where monensin is administered to a subject with a disease or condition involving granulocytes and mast cells as a processing and enzymatic activation inhibitor. See MPEP 2111.02, MPEP 2131.02. Regarding the limitation of claim 24 wherein monensin induces apoptosis in granulocytes, MPEP 2112.02 states” The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978)”and MPEP 2106.04(b)(I).
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 22-25, 27-28, and 36-39 are rejected under 35 U.S.C. 103 as being unpatentable over Gullberg (Processing of Human Cathepsin G after Transfection to the Rat Basophilic/Mast Cell Tumor Line RBL) in view of Bartunek (WO 2015/014329 Al).
The instant claims are directed to a method of administering monensin to a subject for the intended use of treating condition or disease mediated by granulocytes comprising acidic cytoplasmic granules in a subject in need thereof wherein the granulocytes are mast cells and/or eosinophils and wherein the condition or disease is an inflammatory condition or disease.
Gullberg et al. teach azurophil granules of neutrophil granulocytes contain neutral proteases such as cathepsin G and further discloses rat basophilic/mast cell tumor line RBL-1 and that the compound monensin inhibits processing and enzymatic activation of human cathepsin G transfected to rat RBL-1 cells, is proteolytically processed into enzymatically active forms and that subcellular transfer to granular organelles occurs. As the processing of transgenic human cathepsin G corresponds to that of endogenous protease of myeloid cells, the model should provide new unique possibilities to further characterize the activation and granular targeting of myeloid serine proteases. (Abstract, pg. 25219, 1st para).
However, Gullberg et al. fail to disclose a method of administering monensin to a subject in need thereof.
Bartunek et al. teach novel biological activities of monensin, an antibiotic isolated from Streptomyces cinnamonensis and its use in a pharmaceutical composition comprising monensin or its pharmaceutically acceptable salt for treating diseases associated with the deregulated Wnt signaling pathway, preferably intestinal diseases, more preferably familial adenomatous polyposis, colon cancer, rectal cancer and colorectal carcinoma (Abstract). Bartunek also teaches that monensin inhibits androgen signaling and induces apoptosis in prostate cancer cells (pg. 3, lines 23-24). Bartunek also teaches “active substance is present in the pharmaceutical composition together with excipients, such as fillers, disintegrators, diluents, solvents, binders, emulsifying agents, buffers, stabilizing agents, preservatives and colouring agents. The excipients and their use are well known to those skilled in the art. The pharmaceutical compositions comprising monensin or its pharmaceutically acceptable salt can be formulated for systemic administration, e.g. enteral administration, such as oral administration, e.g. in the form of tablets or capsules, for rectal administration, e.g. in the form of suppositories, for nasal administration or for inhalation, e.g. in the form of spray or drops. The compositions according to the invention can be formulated for parenteral administration, such as via injection (i.v., i.m., s.c.), infusion or implanted reservoir system. It is obvious for a person skilled in the art that this specification is not exhaustive, and other appropriated methods of administration will be known to a skilled person. Monensin can be comprised in the pharmaceutical composition in combination with other active substances, for example with a compound exhibiting synergistic effects. The determination of the dosage of the monensin as an active substance in unit dosage form, e.g. in the capsule, or e.g. suitable concentration in solution for injection or infusion is also a routine procedure known to a skilled person.” (sic)(pg. 6, line 27-, pg. 7, line 14).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to administer monensin to a subject in need thereof by combining Gullberg’s disclosure of administering monensin as a method of treating a mast cell disease or condition while looking towards Bartunek’s methods of administering monensin for the treatment of cancer in a subject.
A person of ordinary skill in the art would have been motivated to optimize Gullberg’s method of administering monensin to a subject to inhibit processing and enzymatic activation of cathepsin G in a rat basophilic/mast cell line RBL-1 by adapting the methods of monensin administration taught by Bartunek because the disclosure of monensin’s ability to cause apoptosis in a cancer cells would have given a skilled artisan a reasonable expectation of success in treating a condition or disease mediated by granulocytes comprising mast cells or eosinophils.
Claims 22, 26, 28, 31-33, 35 and 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Gullberg (Processing of Human Cathepsin G after Transfection to the Rat Basophilic/Mast Cell Tumor Line RBL) in view of Huang (US 2010/0075923 A1).
The instant claims are directed to a method of administering monensin to a subject for the intended use of treating condition or disease mediated by granulocytes comprising acidic cytoplasmic granules in a subject in need thereof wherein the granulocytes are mast cells and/or eosinophils and wherein the condition or disease is a type I hypersensitivity.
Gullberg et al. teach azurophil granules of neutrophil granulocytes contain neutral proteases such as cathepsin G and further discloses rat basophilic/mast cell tumor line RBL-1 and that the compound monensin inhibits processing and enzymatic activation of human cathepsin G transfected to rat RBL-1 cells, is proteolytically processed into enzymatically active forms and that subcellular transfer to granular organelles occurs. As the processing of transgenic human cathepsin G corresponds to that of endogenous protease of myeloid cells, the model should provide new unique possibilities to further characterize the activation and granular targeting of myeloid serine proteases. (Abstract, pg. 25219, 1st para).
However, Gullberg et al. fail to disclose the type I hypersensitivity condition of asthma or treating an inflammatory disease or condition with monensin.
Huang et al. teach Monensin is a monovalent ionophore which inhibits clathrin-dependent endocytosis by dissipating a proton gradient [0043]. Huang also teaches a method of treating a condition characterized by decreased TGF-B signaling. Conditions characterized by decreased TGF-B signaling include, but are not limited to inflammatory conditions, autoimmune diseases, cancer, cardiovascular disease and certain skin conditions. In certain embodiments, the inflammatory condition is selected from the group consisting of asthma and atherosclerosis [0023]. Huang also teaches FIG. 1 shows enhancement of TGF-B-stimulated Smad3 phosphorylation and nuclear localization by clathrin-dependent endocytosis inhibitors in Mv1Lu cells wherein 40 μM monensin is (C).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to administer monensin to a subject for the treatment of cancer as disclosed by Gullberg while looking towards Huang who teaches monensin is effective at treating an inflammatory condition, the type I hypersensitivity of asthma, atherosclerosis, or a cardiovascular disease as well as cancer. Furthermore, a skilled artisan seeking to improve an inflammatory condition in a subject would have found it obvious to administer an antihistamine as an additional active agent. See MPEP 2144.05(II).
A person of ordinary skill in the art would have been motivated to administer monensin to a subject with an inflammatory condition, the type I hypersensitivity of asthma, atherosclerosis, or a cardiovascular disease or cancer due to the reasonable expectation of successfully treating said diseases in a subject following the disclosures of Gullberg and Huang.
Conclusion
Claims 22-41 are rejected. No claims are currently allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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/E.V./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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