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 .
Claim Objections
Claim 6 is objected to because of the following informalities: An extra period is at the end of claim 6. Appropriate correction is required.
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.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 112
Claims 1-20 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 particular, the phrase “generic substitution” in the independent claims renders the claims indefinite. This phrase is not defined in the Specification such that the metes and bounds of generic versus non-generic are not clear.
Claim Rejections – 35 USC § 112 (Scope of Enablement)
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 1-20 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 mitigation of symptoms relating to certain cardiovascular conditions, does not reasonably provide enablement for treating ALL neurodegenerative diseases with voriconazole, or an analog or variant thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to treat a subject population having a claimed condition with any analog or variant. Treatment of some neurodegenerative conditions are known in the art, as set forth, e.g., in the cited prior art and such treatment is shown with voriconazole itself.
In particular this Scope of Enablement Rejection applies to the following: Treatment of all neurodegenerative conditions with any analog or variant of claimed compound with “generic substitution.”
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:
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
The instant claims are drawn to treating all neurodegenerative conditions, which includes ALS, Parkinson’s disease, MS, Huntington’s disease, Friedreich’s ataxia, Spinal Muscular Atrophy, Dementia with Lewy Bodies, and others. Treatment of these conditions once a subject has been identified is broad.
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 invitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. what compounds can treat which specific diseases/conditions by what mechanism). There is no absolute predictability even in 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 and treat one of ordinary skill in the art from accepting any therapeutic regimen on its face.
The instantly claimed invention is highly unpredictable as discussed below: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) 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 the distinct nature of neurodegenerative conditions, generally.
The Amount of Direction / Guidance Present and the Presence or Absence of Working Examples
The Examples in the Specification begin on page 42. The examples focus on reducing Cyp46a1 and treating AD or ischemia in mice with voriconazole. There are no other variants, analogs, or neurodegenerative conditions described. As such, we fill in the gaps with the state of the art and the knowledge already in the art. The treatment of cerebral ischemia and Alzheimer’s disease are enabled as is voriconazole.
The level of the skill in the art
The level of skill in the art is high. However, due to the unpredictability in the pharmaceutical art as described above, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by 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 and physiological activity, more teaching or guidance is required. In re Fishcher, 427 F.2d 839, 166 USPQ 24; Ex Parte Hitzeman, 9 USPQ 2d 1823.
The quantity of experimentation needed
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to definitively determine the specific population of individuals who would need to be treated and would furthermore have to determine which of the claimed compounds would provide for the prevention and treatment of all neurodegenerative conditions would require undue experimentation to both develop an animal model which would reasonably correlate with all forms of neurodegenerative diseases and also to identify the portion of the population in which the instantly claimed compounds would need to necessarily be administered.
The cited prior art teaches treatment of specific conditions with voriconazole. There is no reason to believe that voriconazole treats all neurodegenerative conditions. Further, there is no reason to believe that all variants and analogs treat any neurodegenerative condition. The sole agent described in the Specification in an example or an assay is voriconazole. The sole conditions evaluated with a model include AD and cerebral ischemia.
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 chemical nature of the invention, and the lack of working examples regarding the activity of the claimed compounds, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate in scope with the claims.
The court in Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001, states that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection 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 skill in the art would have to engage in undue experimentation to test which diseases can be treated or prevented by the compound encompassed in the instant claims, with no assurance of success.
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.
(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 1-5, 10, 12, and 14-18 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Pikuleva et al., (US20100075991).
Pikuleva teaches compounds and methods for regulating CYP46A1 activity in the brain and retina. Such compounds can be used to treat pathoneurological conditions associated with increased cholesterol levels. See Abstract. Voriconazole is a compound that inhibits CYP46A1 in the mouse brain. See Figures 6A-6D. Dosages were administered via IP injection and were administered as a solution, e.g. See par.’s 25 and 77. Conditions that are associated with an increased level of cholesterol in the brain are Alzheimer’s disease, among others. See par. 50. Voriconazole is taught to be an efficient inhibitor of brain cholesterol. See par. 74. Pharmaceutically acceptable carriers are contemplated. See par. 47. Delivery vehicles are described as well. See par. 52.
Absent evidence to the contrary, the forms are titratable. As described a suitable dosage level will depend on a variety of factors and can be determined by the person administering. See par. 53.
Claims 1-5, 10, 12, and 14-18 are anticipated by the prior art.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-12 and 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over Pikuleva et al., (US20100075991), in view of Hopper et al., (US20220332699) (filed May 24, 2020), and in view of Henry et al., “Quantification of Brain Voriconazole Levels in Healthy Adults Using Fluorine Magnetic Resonance Spectroscopy,” Antimicrobial Agents and Chemotherapy p. 5271–5276 November 2013.
Pikuleva teaches compounds and methods for regulating CYP46A1 activity in the brain and retina. Such compounds can be used to treat pathoneurological conditions associated with increased cholesterol levels. See Abstract. Voriconazole is a compound that inhibits CYP46A1 in the mouse brain. See Figures 6A-6D. Dosages were administered via IP injection. See par. 25. Conditions that are associated with an increased level of cholesterol in the brain are Alzheimer’s disease, among others. See par. 50. Voriconazole is taught to be an efficient inhibitor of brain cholesterol. See par. 74.
Absent evidence to the contrary, the forms are titratable. As described a suitable dosage level will depend on a variety of factors and can be determined by the person administering. See par. 53.
Hopper teaches a methods of treating or preventing disorders by administering compounds that inhibit CYP46A1. See Abstract. Findings have suggested that CYP46A1 inhibitors may be promising treatments for diseases including Alzheimer’s disease, traumatic brain injury, and cerebral infarction. See par. 2. Compounds can be administered orally, intranasally, parenterally, and through other routes. See par. 41. Further, the form can be a liquid solution or suspension, pill, tablet, and other solid form. See par. 45. Further, compounds can be administered in combination with other active agents and the combination can proceed by any technique apparent to those in the art, including separate, sequential, and concurrent administration. See par. 62. Secondary therapeutic agents include NSAIDs including aspiring (par. 82) and platelet aggregation inhibitor (par. 92), among many others.
Henry is cited merely to show that voriconazole is known to cross the blood-brain barrier even when administered orally. See Abstract.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to combine the teachings of Pikuleva, Hopper, and Henry to arrive at the claimed methods. One would be motivated to do so because voriconazole is a known CYP46A1 inhibitor that has such effect in the brain of a subject and can treat Alzheimer’s disease among other conditions, as taught by Pikuleva. Further, this can occur through various routes of administration with numerous carriers and/or excipients. Even further, Hopper teaches treating conditions including Alzheimer’s disease, traumatic brain injury, and cerebral infarction by administering an agent that inhibits CYP46A1. Combination therapy is contemplated and the route of administration and form of drug is not particularly determinative to treatment. Moreover, Henry is cited merely to show that voriconazole effectively crosses the blood brain barrier. Overall, the administration of claimed API is known to effectuate a mechanism of action that will treat the claimed conditions and administration can be in combination with various secondary agents through various routes of administration. The particular dosing regimen would be routinely optimizable in view of the known APIs and the routes of administration as well as mechanism of action by which treatment is expected to occur.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Pikuleva et al., (US20100075991), in view of Hopper et al., (US20220332699) (filed May 24, 2020), and in view of Henry et al., “Quantification of Brain Voriconazole Levels in Healthy Adults Using Fluorine Magnetic Resonance Spectroscopy,” Antimicrobial Agents and Chemotherapy p. 5271–5276 November 2013, and in view of Steiner et al., (US2010/0298394).
Pikuleva teaches compounds and methods for regulating CYP46A1 activity in the brain and retina. Such compounds can be used to treat pathoneurological conditions associated with increased cholesterol levels. See Abstract. Voriconazole is a compound that inhibits CYP46A1 in the mouse brain. See Figures 6A-6D. Dosages were administered via IP injection. See par. 25. Conditions that are associated with an increased level of cholesterol in the brain are Alzheimer’s disease, among others. See par. 50. Voriconazole is taught to be an efficient inhibitor of brain cholesterol. See par. 74.
Hopper teaches a methods of treating or preventing disorders by administering compounds that inhibit CYP46A1. See Abstract. Findings have suggested that CYP46A1 inhibitors may be promising treatments for diseases including Alzheimer’s disease, traumatic brain injury, and cerebral infarction. See par. 2. Compounds can be administered orally, intranasally, parenterally, and through other routes. See par. 41. Further, the form can be a liquid solution or suspension, pill, tablet, and other solid form. See par. 45. Further, compounds can be administered in combination with other active agents and the combination can proceed by any technique apparent to those in the art, including separate, sequential, and concurrent administration. See par. 62. Secondary therapeutic agents include NSAIDs including aspiring (par. 82) and platelet aggregation inhibitor (par. 92), among many others.
Henry is cited mere to show that voriconazole is known to cross the blood-brain barrier even when administered orally. See Abstract.
Steiner teaches using biomarker assays to identify subjects with pre-clinical conditions including Alzheimer’s disease and treating them with neuroprotective agents including voriconazole. See par.’s 110-112 and Table 1. Steiner uses prognostic biomarkers to predict risk of developing a condition, e.g. See par. 206. Conditions to be treated (i.e., protected against) and identified include Alzheimer’s disease and voriconazole as preferred. See prior art claims 4 and 11.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to combine the teachings of Pikuleva, Hopper, Henry, and Steiner to arrive at the claimed methods. One would be motivated to do so because voriconazole is a known CYP46A1 inhibitor that has such effect in the brain of a subject and can treat Alzheimer’s disease among other conditions, as taught by Pikuleva. Further, this can occur through various routes of administration with numerous carriers and/or excipients. Even further, Hopper teaches treating conditions including Alzheimer’s disease, traumatic brain injury, and cerebral infarction by administering an agent that inhibits CYP46A1. Combination therapy is contemplated and the route of administration and form of drug is not particularly determinative to treatment. Moreover, Henry is cited merely to show that voriconazole effectively crosses the blood brain barrier. Overall, the administration of claimed API is known to effectuate a mechanism of action that will treat the claimed conditions and administration can be in combination with various secondary agents through various routes of administration. The particular dosing regimen would be routinely optimizable in view of the known APIs and the routes of administration as well as mechanism of action by which treatment is expected to occur. Even further, Steiner teaches using biomarker assays to identify subjects with pre-clinical conditions including Alzheimer’s disease and treating them with neuroprotective agents including voriconazole.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628