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 .
Status of the Claims
Claims 1-15 are pending and examined.
Information Disclosure Statement
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 Objections
Claim 1 is objected to because of the following informalities: In claim 1, line 2, “patent” should read “patient.” Appropriate correction is required. Claim 8 is objected to because of the following informalities: In claim 8, line 1, “claims” should read “claim.” Appropriate correction is required. Claim 14 is objected to because of the following informalities: In claim 14, line 2, “comprises” should read “comprising.” Appropriate correction is required.
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.
Claim 14 is 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 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. This is a written description rejection. The following reasons apply:
Claim 14 is directed to a method of administering belumosudil wherein the patient has been administered one more immunosuppressive agents comprises cyclosporine, tacrolimus, sirolimus; prednisone; or an inhibitor of nucleic acid synthesis. Thus, the claims encompass a genus of pharmaceutical compositions which functions as an inhibitor of nucleic acid synthesis. Inhibitors of nucleic acid synthesis can be small molecules, polypeptides, peptides, glycoproteins, peptide-mimetics, DNA, RNA, RNAi, siRNA, shRNA, and CRISP/Cas9 constructs.
The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other 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 applicant was in possession of the claimed genus.” (Federal register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001, see especially page 1106 column 3) and (see MPEP 2164).
In review of the instant Specification, the Specification does not appear to provide guidance as to what structural components are critical to the desired function. The Specification does not test the efficacy of any inhibitors of nucleic acid synthesis. Since there are an innumerably large number of biomolecules/compounds within the scope of the generic claim, it would require extensive manpower to make and test each compound to determine which compound would possess the recited properties (i.e., function as an inhibitor of nucleic acid synthesis) and be useful in the instantly claimed treatment of GVHD.
Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and demonstrate that by disclosure in the specification of the patent.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003).
Written description requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed. A patentee can lawfully claim only what he has invented and described, and if he claims more his patent is void.
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 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co.,43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written
description to identify the genus of the claim. In Regents of the University of California, the
court stated, “A written description of an invention involving a chemical genus, like a description
of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical
name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984
F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985
(CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is
unpredictability in performance of certain species or subcombinations other than those
specifically enumerated, one skilled in the art may be found not to have been placed in
possession of a genus…”) Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d
1398.
The MPEP further states that if a biomolecule is described only by a functional
characteristic, without any disclosed correlation between function and structure, it is “not
sufficient characteristic for written description purposes, even when accompanied by a method of
obtaining the claimed sequence.” MPEP §2163. The MPEP does state that for a generic claim the
genus can be adequately described if the disclosure presents a sufficient number of representative
species that encompass the genus. MPEP §2163. If the genus has a substantial variance, the
disclosure must describe a sufficient variety of species to reflect the variation within that genus.
See MPEP §2163. Although the MPEP does not define what constitutes a sufficient number of
species, the courts have indicated what do not constitute a representative number of species to
adequately describe a broad generic. In In re Gostelli, the courts determined that the disclosure
of two chemical compounds within a subgenus did not describe that subgenus. 872, F.2d at 1012,
10 USPQ2d at 1618.
In the instant case, the claim is drawn to a method of administering belumosudil wherein the patient has been administered one immunosuppressive agents comprises cyclosporine, tacrolimus, sirolimus; prednisone; or an inhibitor of nucleic acid synthesis. Thus, the claims encompass a genus of molecules which function as an inhibitor of nucleic acid synthesis. The claim is generic, broadly reciting a genus of “inhibitor of nucleic acid synthesis.”
As stated supra, the MPEP states that written description for a genus can be satisfied by a
representative number of species. It is unquestionable that claim 14 is broad and
generic, with respect to all possible compounds encompassed by the claims.
Applicant has failed to show that they were in possession of all the diverse compounds encompassed by an inhibitor of nucleic acid synthesis. The possible variation of any molecule that functions as an inhibitor of nucleic acid synthesis within the scope of claim 14 is limitless and would encompass compounds that function as inhibitors of nucleic acid synthesis not yet discovered. In a review of the specification applicant does not disclose any species of inhibitors of nucleic acid synthesis. Since there are an innumerably large number of
biomolecules/compounds within the scope of the generic claims, it would require extensive
manpower to make and test each compound to determine which compound would possess the
recited properties (i.e., function as an inhibitor of nucleic acid synthesis) and be useful in the instantly claimed method.
Given the broad scope of the claimed subject matter, Applicant has not provided
sufficient written description that would allow the skilled in the art to recognize all the
compounds claimed to be useful in the method of claims 14.
It is suggested to amend the claims to represent the embodiments in the Specification that were possessed at the time of the filing.
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 9-10 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 hematopoietic stem cells and kidney cells, does not reasonably provide enablement for heart cells, intestinal cells, liver cells, lung cells, pancreatic cells, face cells, hand cells or reproductive organ cells. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to select a patient for belumosudil administration wherein the patient is selected for a transplantation of heart cells, intestinal cells, liver cells, lung cells, pancreatic cells, face cells, hand cells, or reproductive organ cells. This is a scope of enablement rejection.
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), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
The nature of the invention
The state of the prior art
The predictability or lack thereof in the art
The amount of direction or guidance present
The presence or absence of working examples
The breadth of the claims
The quantity of experimentation needed, and
The level of skill in the art.
The Nature of the Invention
Instant claims 9-10 are drawn to administering belumosudil comprising selecting a patient for belumosudil administration, wherein the patient is selected for a transplantation procedure with one or more genetically non-identical cells, tissues or organs; and administering belumosudil to the patient, wherein the belumosudil is administered following transplantation and prior to the diagnosis or onset of graft versus host disease in the patient. Claim 9 is further drawn to the method of administering belumosudil wherein the one or more genetically non-identical cells, tissues or organs comprise at least one of: hematopoietic stem cells, kidney cells, heart cells, intestinal cells, liver cells, lung cells, pancreatic cells, face cells, hand cells, or reproductive organ cells. Claim 10 is further drawn to a method of administering belumosudil wherein the one or more genetically non-identical cells, tissues or organs comprise at least two of: hematopoietic stem cells, kidney cells, heart cells, intestinal cells, liver cells, lung cells, pancreatic cells, face cells, hand cells, or reproductive organ cells. The administration of belumosudil following transplantation of intestinal cells, lung cells, pancreatic cells, face cells, hand cells, or reproductive organ cells, is unknown.
The State of the Prior Art and the Predictability or lack thereof in the art
The state of the prior art is that the pharmacological art involves screening in vitro and in vivo to determine which subject populations would therapeutically benefit from administration of belumosudil following tissue transplant (i.e., which cell/tissue transplants would the administration of belumosudil be appropriate and/or efficacious for). There is no absolute predictability even in the view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting the transplantation of any cell/tissue type on its face.
The instantly claimed invention is highly unpredictable as discussed below: It is noted that the pathophysiological art is unpredictable, requiring each embodiment of tissue/cell type to be individually assessed for physiological activity. The symptomology and development of GVHD depends on the type on target tissues transplanted, as set forth in the following references.
Ghimire et al., “Pathophysiology of GvHD and Other HSCT-Related Major Complications,” Frontiers in Immunology, Alloimmunity and Transplantation, 2017. Indeed, different cell types demonstrate varying levels of sensitivity and susceptibility to the development of GVHD. Ghimire et al., 2017. Organ-specific chemokines drive the migration of immune cells and pro-inflammatory responses which underly the development of GVHD.
Kuba et al., “Graft versus Host Disease: From Basic Pathogenic principles to DNA Damage Response and Cellular Senescence,” Mediators of Inflammation, 2018.
In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 170) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instantly claimed invention is highly unpredictable since one skilled in the art would recognize that in regards to transplantation of the instantly claimed cell/tissue types, and whether or not administration of belumosudil would be selected for administration in following transplantation of the instantly claimed cell/tissue types would be appropriate. There are no examples in the instant specification that provide support that belumosudil administration would be appropriate following transplantation of heart cells, intestinal cells, liver cells, lung cells, pancreatic cells, face cells, hand cells, or reproductive organ cells.
The Amount of Direction / Guidance Present and the Presence or Absence of Working Examples
The Specification provides multiple examples of the transplantation of hematopoietic stem cells and kidney cells. However, there are no examples that demonstrate the administration of belumosudil following transplantation of heart cells, intestinal cells, liver cells, lung cells, pancreatic cells, face cells, hand cells, or reproductive organ cells.
The Level of Skill in the Art
The level of skill in the art is high. However, due to unpredictability in the pharmaceutical and pathophysiological art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity in vitro and in vivo screening to determine whether the compound exhibits the desired pharmacological activity. The amount of guidance or direction needed to enable the invention is inversely related to the degree of predictability in the art. In re Fisher, 839, 166 USPQ 24. Thus, although a single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements, in cases involving unpredictable factors, such as most chemical reactions or physiological activity, more teaching or guidance is required. In re Fisher, 427 F2d 839, 166 UPSQ 24, Ex Parte Hitzeman, 9 USPQ 2d 1823.
Thus, the Specification fails to provide sufficient support of the broad method of the instant claims for the administration of belumosudil following transplantation of any one or more of heart cells, intestinal cells, liver cells, lung cells, pancreatic cells, face cells, hand cells, or reproductive organ cells. As a result, it is not clear the efficacious administration of belumosudil following transplantation of any one or more of heart cells, intestinal cells, liver cells, lung cells, pancreatic cells, face cells, hand cells, or reproductive organ cells will be possible.
The Quantity of Experimentation Needed
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to test the administration of belumosudil following transplantation in each claimed cell type: heart cells, intestinal cells, liver cells, lung cells, pancreatic cells, face cells, hand cells, or reproductive organ cells.
Thus, factors such as “sufficient working examples,” “the level of skill in the art” and “predictability,” etc. have been demonstrated to be sufficiently lacking in the instantly claimed methods. In view of the breadth of the claim, the pharmacological and physiological natures of the method, and the lack of working examples regarding the activity of the claimed method in vivo, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate to the scope of the claims.
Genetech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ 2d 1001, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent prosecution is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of ordinary skill in the art would have to engage in undue experimentation to identify the claimed subject population, with no assurance of success.
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.
Claims 1-15 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.
Claim 1 recites “prior to the diagnosis or onset of graft versus host disease in the patient.” The phrase “prior to the diagnosis or onset of graft versus host disease in the patient” is indefinite. It is unclear to the examiner how applicant distinguishes patients who, have undergone a transplant and have been diagnosed or undergone the onset of GVHD, from patients who, have undergone a transplant and have not been diagnosed or displayed an onset of GVHD. The meaning of every term used in a claim should be apparent from the prior at or from the specification and drawings at the time the application is filed. Claim language may not be “ambiguous, vague, incoherent, opaque, or otherwise unclear in describing and defining the claimed invention.” In re Packard, 75 F.3d 1307, 1311, 110 USPQ2d 1785, 1787 (Fed. Cir. 2014). The examiner proposes the following language if supported in the instant specification, “wherein the belumosudil is administered following transplantation to patients at risk for graft versus host disease.”
Claims 2-14, which are dependent on claim 1, are similarly rejected under 35 U.S.C. 112(b).
Claim 6 recites the limitation, “the one or more genetically non-identical donor tissues or organs.” There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not refer to a “one of more genetically non-identical donor tissues or organs,” and it is unclear what donor tissues or organs the applicant is referring to.
Claim 15 draws to a use in the treatment of graft versus host disease prior to the onset of graft versus host disease but does not set forth any steps involved in the process of use. See MPEP 2173.05(q). Claims which recite a use without setting forth any active, positive steps delimiting how the use is actually practiced are indefinite under 112(b). Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986). One cannot rely on the specification to impart limitations to the claim that are not recited in the claim. Although the instant specification may enlighten active steps for the use of belumosudil, it is improper to read limitations contained in the specification into the claims. See, In re Prater, 415 F.2d 1393, 162 USPQ 541 (CCPA 1969) and In re Winkhaus, 527 F.2d 637, 188 USPQ 129 (CCPA 1975).
Further, claim 15 recites the phrase, “prior to the diagnosis or onset of graft versus host disease in the patient” is indefinite. Again, it is unclear to the examiner how applicant distinguishes patients who, have undergone the onset of GVHD, from patients who, have not undergone an onset of GVHD.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 13-14 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 13 draws to the method of claim 1, wherein the patient has not undergone a previous transplantation procedure with one or more genetically non-identical cells, tissues or organs. However, claim 1 is drawn to a method of administering belumosudil comprising administering belumosudil to the patient, wherein the belumosudil is administered following transplantation and prior to the diagnosis or onset of graft versus host disease in the patient. As written, claim 13 contradicts the limitations of claim 1 and thus, does not limit the scope of claim 1.
Claim 14, which is dependent on claim 13, is similarly rejected under 35 U.S.C. 112(d).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1, 3, 4, 6, 9-13, and 15 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated, by Schwartz, et al., (US20160361300A1).
Regarding claim 1, Schwartz teaches a method of administering belumosudil. See Specification. According to some embodiments, the described invention provides a therapeutic amount of one or more ROCK inhibitor compounds of an active ingredient of a pharmaceutical composition and ROCK inhibitor compounds include SLx-2119. See Specification, paragraph 0192, lines 1-3. Schwartz further teaches the method of claim 1 comprising (a) selecting a patient for belumosudil administration wherein the patient is selected for a transplantation procedure with one or more genetically non-identical cells, tissues or organs; and (b) administering belumosudil to the patient, wherein the belumosudil is administered following transplantation and prior to the diagnosis or onset of graft versus host disease in the patient. See Abstract and Specification. The described invention related to methods for preventing or treating graft-versus-host-disease in a patient with a tumor receiving a transplant. See Abstract. According to some embodiments, the transplant is allogenic and according to some embodiments, the transplant is xenogeneic. See Specification, paragraph [0071], lines 1-2.
Regarding claim 3, Schwartz teaches the method of claim 1, wherein belumosudil is administered within 3 months of the patient being transplanted with one or more genetically non-identical cells, tissues, or organs. See Specification. For some embodiments, following transplantation, the dual mode of administration was started one or two days prior to irradiation and continued for 10 days post-transplant. See Specification, paragraph 0257, lines 7-8.
Regarding claim 4, Schwartz teaches the method of claim 3, wherein the belumosudil is administered within one month of the patient being transplanted with one or more genetically identical cells, tissues or organs. See Specification. For some embodiments, following transplantation, the dual mode of administration was started one or two days prior to irradiation and continued for 10 days post-transplant. See Specification, paragraph 0257, lines 7-8.
Regarding claim 6, Schwartz teaches the method of claim 1, wherein the one or more genetically non-identical donor tissues or organs comprise at least one human leukocyte antigen that is mismatched with at least one human leukocyte antigens present in the patient. In some embodiments, the animal undergoing allogenic HSC transplantation from a related or unrelated donor matched at least 7 out of 8 of the HLA-A, -B, -C and -DR. See Specification, paragraph 0303, lines 1-4. Therefore, some animals had a mismatch at either HLA-A, -B, -C and -DR.
Regarding claim 9, Schwarts teaches the method of claim 1, wherein the one or more genetically non-identical cells, tissues or organs comprise at least one of: hematopoietic stem cells, kidney cells, heart cells, intestinal cells, liver cells, lung cells, pancreatic cells, face cells, hand cells, or reproductive organ cells. See Specification. In some embodiments, transplants include both allogeneic or xenogeneic hematopoietic cells. See Specification, paragraph 0092, lines 8-9. Further, the term ‘graft’ as used herein, refers to any tissue or organ for transplantation. See Specification, paragraph 117, lines 1-2.
Regarding claim 10, Schwartz teaches the method of claim 1, wherein the one or more genetically non-identical cells, tissues or organs comprise at least two of: hematopoietic stem cells, kidney cells, heart cells, intestinal cells, liver cells, lung cells, pancreatic cells, face cells, hand cells, or reproductive organ cells. See specification. Transplants include allogeneic or xenogeneic hematopoietic cells, tissue grafts, including solid organs. See Specification, Paragraph 0092, lines 7-8.
Regarding claim 11, Schwartz teaches the method of claim 1, wherein the one or more genetically non-identical cells, tissues or organs consists essentially of hematopoietic stem cells. See specification. Transplants include allogeneic or xenogeneic hematopoietic cells. See Specification, Paragraph 0092, line 7.
Regarding claim 12, Schwartz teaches the method of claim 1, wherein the one or more genetically non-identical cells, tissues or organs consists essentially of kidney cells. See Specification. the term ‘graft’ as used herein, refers to any tissue or organ for transplantation. See Specification, Paragraph 0117, line 1-2.
Regarding claim 13, Schwartz teaches the method of claim 1, wherein the patient has not undergone a previous transplantation procedure with one or more genetically identical cells, tissues, or organs. During experimentation, adult male C3B6 mice exposed to lethal irradiation received anti-T cell treated bone marrow transplant (ATBM) from donor C3H mice. See specification, paragraph 0257.
Regarding claim 15, Schwartz teaches belumosudil for use in the treatment of graft versus host disease prior to the onset of graft versus host disease. See Title and Specification. The invention involves a method to prevent and treat graft versus host disease. See Title. According to some embodiments, the described invention provides a therapeutic amount of one or more ROCK inhibitor compounds of an active ingredient of a pharmaceutical composition, and ROCK inhibitor compounds include SLx-2119. See Specification, paragraph 192, lines 1-3.
Claim Rejections - 35 USC § 103
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 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.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Schwartz as applied to claim 1 above, and further in view of Bockermann et al., (WO2021175914A1).
Schwartz teaches a method of administering belumosudil. See Specification. According to some embodiments, the described invention provides a therapeutic amount of one or more ROCK inhibitor compounds of an active ingredient of a pharmaceutical composition and ROCK inhibitor compounds include SLx-2119. See Specification, paragraph 0192, lines 1-3. Schwartz further teaches the method of claim 1 comprising (a) selecting a patient for belumosudil administration wherein the patient is selected for a transplantation procedure with one or more genetically non-identical cells, tissues or organs; and (b) administering belumosudil to the patient, wherein the belumosudil is administered following transplantation and prior to the diagnosis or onset of graft versus host disease in the patient. See Abstract and Specification. The described invention related to methods for preventing or treating graft-versus-host-disease in a patient with a tumor receiving a transplant. See Abstract. According to some embodiments, the transplant is allogenic and according to some embodiments, the transplant is xenogeneic. See Specification, paragraph [0071], lines 1-2.
Schwartz further teaches wherein the administration of belumosudil to the patient occurs in conjunction with a transplantation conditioning regimen. See Specification. According to one aspect the described invention involves treating the patient with a therapeutically effective regimen to reduce the GVHD progression. See Specification, paragraph 0078, lines 10-11. Further, Schwartz teaches a pre-transplant conditioning regimen. See, Specification, paragraph 0293, line 12. Schwartz fails to teach the transplantation condition regimen comprising anti-thymocyte globulin (rATG) administration and total lymphoid irradiation (TLI).
However, Bockermann teaches wherein the transplantation conditioning regimen comprising anti-thymocyte globulin (rATG) administration and total lymphoid irradiation (TLI). See, Summary of the invention and Claims. Claim 8 teaches the conditioning regimen of claim 7 comprising the administration of rATG. See claim 8. Further, Bockermann teaches the conditioning regimen may additionally comprise administration of a non-lethal dose of irradiation and that total body irradiation was given. Naturally, total body irradiation encompasses total lymphoid irradiation.
Schwartz and Bockermann are analogous to the claimed invention because both are in the same field of treating GVHD following transplantation. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of administering belumosudil in conjunction with a transplant conditioning regimen of Schwartz by substituting the transplant conditioning regimen of Bockermann. The simple substitution of the known elements is likely to be obvious when predictable results are achieved. See, KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, B.).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application that anti-thymocyte globulin (rATG) administration and total lymphoid irradiation (TLI) would be an effective transplant conditioning regimen. One would be motivated to do so because there is a need to identify novel transplant conditioning regimens which are efficacious in treating GVHD in conjunction with belumosudil administration following transplantation. Further, the use of the claimed agent and the claimed conditioning regimen are each taught to independently prevent and/or treat a subject that has or is at risk of a transplant-associated condition. As such, there is a reasonable and predictable expectation of success in arriving at the transplant conditioning regimen in conjunction with belumosudil administration in view of the teachings of the cited prior art.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Schwartz as applied to claim 1 above, and further in view of Reisner et al., (US2019/091266A1).
Schwartz teaches a method of administering belumosudil. See Specification. According to some embodiments, the described invention provides a therapeutic amount of one or more ROCK inhibitor compounds of an active ingredient of a pharmaceutical composition and ROCK inhibitor compounds include SLx-2119. See Specification, paragraph 0192, lines 1-3. Schwartz further teaches the method of claim 1 comprising (a) selecting a patient for belumosudil administration wherein the patient is selected for a transplantation procedure with one or more genetically non-identical cells, tissues or organs; and (b) administering belumosudil to the patient, wherein the belumosudil is administered following transplantation and prior to the diagnosis or onset of graft versus host disease in the patient. See Abstract and Specification. The described invention related to methods for preventing or treating graft-versus-host-disease in a patient with a tumor receiving a transplant. See Abstract. According to some embodiments, the transplant is allogenic and according to some embodiments, the transplant is xenogeneic. See Specification, paragraph [0071], lines 1-2. Schwartz fails to teach wherein the one or more genetically non-identical cells, tissues or organs are obtained from a deceased donor.
However, Reisner teaches tissue and cells for transplantation wherein the one or more genetically non-identical cells, tissues or organs are obtained from a deceased donor. See par. 38, e.g. Depending on the application and available sources, cells for use according to the present invention may be obtained from a prenatal organism, a postnatal organism, an adult, or a deceased donor. See, Specification, paragraph 31. Stem cells can be derived from skin, liver, kidney, prostate, pancreas, intestine, and other sources. See par. 150.
Schwartz and Reisner are analogous to the claimed invention because they both are in the same field of transplantation tolerance induction. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the one or more genetically non-identical cells, tissues or organs of Schwartz by substituting the cells, tissues or organs with those obtained from a deceased donor. The simple substitution of the known elements is likely to be obvious when predictable results are achieved. See, KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, B.).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application that cells, tissues or organs obtained from a deceased donor would be effective genetically non-identical cells, tissues or organs for transplantation. One would be motivated to do so because there is a need to evaluate the development and progression GVHD following transplantation received from all types of donors. As such, there is a reasonable and predictable expectation of success in arriving at the transplant of non-identical cells tissues or organs obtained from a deceased donor in view of the teachings of the cited prior art.
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Schwartz as applied to claim 1 above, and further in view of Lowsky, (US20200254015A1).
Regarding claim 7, Schwartz teaches a method of administering belumosudil. See Specification. According to some embodiments, the described invention provides a therapeutic amount of one or more ROCK inhibitor compounds of an active ingredient of a pharmaceutical composition and ROCK inhibitor compounds include SLx-2119. See Specification, paragraph 0192, lines 1-3. Schwartz further teaches the method of claim 1 comprising (a) selecting a patient for belumosudil administration wherein the patient is selected for a transplantation procedure with one or more genetically non-identical cells, tissues or organs; and (b) administering belumosudil to the patient, wherein the belumosudil is administered following transplantation and prior to the diagnosis or onset of graft versus host disease in the patient. See Abstract and Specification. The described invention related to methods for preventing or treating graft-versus-host-disease in a patient with a tumor receiving a transplant. See Abstract. According to some embodiments, the transplant is allogenic and according to some embodiments, the transplant is xenogeneic. See Specification, paragraph [0071], lines 1-2. Schwartz fails to teach wherein the one or more genetically non-identical donor tissues or organs comprise at least 2, 3, 4, 5 or 6 human leukocyte antigens that are mismatched with human leukocyte antigens present it the patient.
However, Lowsky teaches wherein the one or more genetically non-identical donor tissues or organs comprise at least 2, 3, 4, 5 or 6 human leukocyte antigens that are mismatched with human leukocyte antigens present it the patient. See, Equivalent Abstract. In the Lowsky invention, the CD34+ cells and the CD3+ cells are HLA mismatched to the solid organ transplant recipient at all six HLA alleles. See, Equivalent Abstract.
Regarding claim 8, Lowsky teaches the method of claim 7 as demonstrated above. Lowsky fails to teach wherein the HLA mismatches occur at least one of: HLA-A, HLA-B, HLA-C, or HLA-DR.
However, it was earlier established above that Schwartz teaches wherein the HLA mismatches occur at least one of HLA-A, HLA-B, HLA-C, or HLA-DR. In some embodiments, the animal undergoing allogenic HSC transplantation from a related or unrelated donor matched at least 7 out of 8 of the HLA-A, -B, -C and -DR. See Specification, paragraph 0303, lines 1-4. Therefore, some animals had a mismatch at either HLA-A, -B, -C and -DR.
Schwartz and Lowsky are analogous to the claimed invention because both are in the same field of transplantation. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the instant application to modify the one or more genetically non-identical donor tissues or organs comprising at least 2, 3, 4, 5 or 6 human leukocyte antigens that are mismatched with human leukocyte antigens with mismatches occurring at HLA-A, -B, -C and -DR. As such, there is reasonable and predictable expectation of success in arriving at the claimed method in view of the teachings of the cited prior art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395-97 (2007) (see MPEP §2143, G).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application that mismatches occurring at HLA-A, -B, -C and -DR could be one of the potential mismatches at the HLA alleles. One would be motivated to do so because there is a need to identify the impact of HLA mismatches, particularly at specific allele loci, on the efficacy of treatment on GVHD. As such, there is reasonable and predictable expectation of success in arriving at the claimed method in view of the teachings of the cited prior art.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Schwartz as applied to claim 1 above, and further in view of Zanin-Zhorov, et al., (WO2015157556A1).
Schwartz teaches a method of administering belumosudil. See Specification. According to some embodiments, the described invention provides a therapeutic amount of one or more ROCK inhibitor compounds of an active ingredient of a pharmaceutical composition and ROCK inhibitor compounds include SLx-2119. See Specification, paragraph 0192, lines 1-3. Schwartz further teaches the method of claim 1 comprising (a) selecting a patient for belumosudil administration wherein the patient is selected for a transplantation procedure with one or more genetically non-identical cells, tissues or organs; and (b) administering belumosudil to the patient, wherein the belumosudil is administered following transplantation and prior to the diagnosis or onset of graft versus host disease in the patient. See Abstract and Specification. The described invention related to methods for preventing or treating graft-versus-host-disease in a patient with a tumor receiving a transplant. See Abstract. According to some embodiments, the transplant is allogenic and according to some embodiments, the transplant is xenogeneic. See Specification, paragraph [0071], lines 1-2.
Schwartz further teaches the method of claim 13 wherein the patient has not undergone a previous transplantation procedure with one or more genetically identical cells, tissues, or organs. During experimentation, adult male C3B6 mice exposed to lethal irradiation received anti-T cell treated bone marrow transplant (ATBM) from donor C3H mice. See specification, paragraph 0257. Schwartz fails to teach wherein the patient has been administered one or more immunosuppressive agents comprises cyclosporine, tacrolimus, sirolimus, prednisone, or an inhibitor of nucleic acid synthesis.
However, Zanin-Zhorov teaches wherein the patient has been administered one or more immunosuppressive agents comprises cyclosporine, tacrolimus, sirolimus, prednisone, or an inhibitor of nucleic acid synthesis. See Specification. The invention relates to treatment of graft versus host disease (GVHD) using compounds that inhibit ROCK2. See Specification, paragraph 0001. In further aspects of the invention, the compound that inhibits ROCK2 is SLx-2119. See Specification, paragraph 0089. In yet another embodiment, a rho-kinase inhibitor of the invention and an immunosuppressant are administered. See, Specification, paragraph 0168. Immunosuppressants include steroid drugs such as glucocorticoids (e.g., dexamethasone), FK506 (tacrolimus), ciclosporin, and fingolimod. See, Specification, paragraph 0179.
Schwartz and Lowsky are analogous to the claimed invention because both are in the same field of treating GVHD with belumosudil. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the instant application to modify method of administering belumosudil from Schwartz by also administering one or more immunosuppressive agents. As such, there is reasonable and predictable expectation of success in arriving at the claimed method in view of the teachings of the cited prior art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395-97 (2007) (see MPEP §2143, G).
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the instant application that belumosudil could be administered in conjunction with one or more immunosuppressive agents including cyclosporine or tacrolimus. One would be motivated to do so because there is a need to evaluate the effects of the combined use of existing treatment regimens for the treatment GVHD. "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). As such, there is reasonable and predictable expectation of success in arriving at the claimed method in view of the teachings of the cited prior art.
Correspondence
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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