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
Pursuant to the preliminary amendment dated 1/17/2024, claims 3, 5, 6, 10-15, 23-33, 35, 38, 40, 43 and 45-52 are cancelled and claims 1, 2, 4, 7, 8, 16-22, 34, 36, 37, 41 and 44 are amended. No claims are newly added.
Claims 1, 2, 4, 7-9, 16-22, 34, 36, 37, 39, 41, 42 and 44 are pending in the instant application and are examined on the merits herein.
Priority
The application is a National Stage entry of PCT/US2021/048072 filed on 8/27/2021, which claims priority to provisional application 63/071222 filed on 8/27/2020.
Information Disclosure Statement
The information disclosure statements (IDS) dated 2/24/2023, 1/2/2024 and 7/26/2024 comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609, except where noted. Accordingly, the IDS documents have been placed in the application file and the information therein has been considered as to the merits.
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 39, 41, 42 and 44 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Vikmon et al. (US 5,403,840; 1995, PTO-892).
Vikmon discloses a pharmaceutical composition consisting essentially of as active ingredient an effective amount of the inclusion complex of N-ethoxycarbonyl-3-morpholino-sydnonimine or its salt formed with hydroxypropyl-beta-cyclodextrin, in a molar ratio of 1:1 to 1:40 and customary pharmaceutical filling, diluting and further auxiliary materials. (Claims 6; Example 4)
With respect to claims that contain language describing the mechanism of action (e.g. reduction of cholesterol crystal properties, increase of oxy sterols levels or increase of levels of ABCA1 or ABCG1) of the claimed cyclodextrin, these claims are rejected due to the inseparable connection between a chemical and its intrinsic properties. Although the prior art is silent in regards to the mechanism of action, products of identical chemical composition cannot have mutually exclusive properties. Therefore, because Vikmon anticipates the composition claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See also MPEP § 2112.01.
Accordingly, the instant claims are anticipated by the prior art.
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 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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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 1, 2, 4, 7-9, 16-19, 21, 22, 34, 39, 41, 42 and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Zimmer et al. (Sci. Trans. Med., 2016, IDS), in view of Ghanem et al. (J. Biomed. Res., 2017, PTO-892).
Zimmer et al. discloses a method for reducing human carotid plaque size and reducing cholesterol crystal amount, by administering 2-hydroxypropyl-beta-cyclodextrin (HP-b-CD). (Abstract, Figures 1A-D, 2D, 7) Zimmer also discloses that HP-b-CD is effective to increase the level of 27-hydroxycholesterol production, by a factor of 3-15, such that HP-b-CD increases the metabolism of free cholesterol and could thereby lower the potential for its phase transition into crystals. (p. 4, Col. 1; Figure 4G-H) Zimmer discloses that HP-b-CD is effective to increase cholesterol crystal dissolution showing reduction in crystal size versus control by almost 50%. (Figure 3F) Zimmer also concludes, “Because CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis”. (Abstract) Zimmer discloses that HP-b-CD was administered at a dose of 2 g/kg. (Figures 2, 6, 8)
Zimmer does not teach: 1) a subject population of individuals at least 30 years old or 2) treating cholesterol crystal embolization.
Ghanem et al. discloses that cholesterol crystal embolization (CCE) refers to the embolization of cholesterol crystals (CCs) released from atherosclerotic plaques lining the walls of the aorta or major inflow arteries that showered particulates downstream via smaller arteries and arterioles to end organs. (p. 82) CCE has been noted to predominantly affect males (age over 60 years) often with clinical evidence of atherosclerotic cardiovascular disease. The true incidence of CCE varies widely due to inconsistency in diagnostic approaches based on the reporting used i.e. clinical (mainly dermal manifestations or elevation in serum creatinine) or histopathological criteria by biopsy.…Patients who underwent myocardial revascularization or valve operations and had evidence of severe atherosclerosis of the ascending aorta were found to have an increased incidence of CCE with 21.7% in the autopsy series…Cholesterol crystal embolization can occur either spontaneously or as a complication of mechanical trauma during aortic surgery, angioplasty and various angiographic procedures such as aortography, left heart catheterization and peripheral angiography. Several predisposing factors have been associated with the development of CCE following cardiac and endovascular procedures. These include hypertension, heavy smoking, hypercholesterolemia, diabetes mellitus, renal failure, advanced age, peripheral vascular disease and severe atherosclerosis of the ascending aorta... Sporadic case reports have hypothesized a causal relationship between CCE and thrombolytic administration for myocardial infarction or deep venous thrombosis. The use of thrombolytic or anticoagulant treatment may facilitate CCE possibly by preventing thrombus formation over ulcerated plaques, promoting plaque hemorrhage or interfering with the stabilization of CCs within atheromatous plaques by platelet-fibrin.(p. 83) Ghanem further discloses that: 1) In an atherosclerotic rabbit model, those with a greater plaque burden had more CCs, serum inflammation, macrophage infiltration and thrombosis (p. 85); and 2) eosinophilia is commonly seen with renal CCE (in up to 80% of patients) but is transient, lasting only a few days. The urine sediment is usually benign (with few cells and a minimum amount of proteinuria) which helps differentiate renal CCE from systemic vasculitis. (p. 87)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the subject population treated in the method of Zimmer/Ghanem would be those at least 30 years old because Ghanem teaches that subjects experiencing CCE are predominantly affect males (age over 60 years). It would have been further obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to extend the HP-b-CD treatment of atherosclerosis of Zimmer, to a subject having, or at risk of having CCE. One of ordinary skill in the art would have been motivated to apply the method of Zimmer in treating CCE because Ghanem teaches that CCE occurs in or is of increased likelihood, in atherosclerotic subjects, due to the formation of atherosclerotic plaques rich with cholesterol crystals that rupture releasing emboli. The administration of HP-b-CD using the method of Zimmer would be expected to reduce the size of cholesterol crystals and increase cholesterol dissolution, which would in turn be expected to reduce the risk of CCE.
With respect to claims 8, 9 and 16-20 and limitations for improving renal function, a dermatologic manifestation, eosinophilia, a hematologic abnormality, or proteinuria, in subjects with CCE, these limitations are met by Zimmer/Ghanem. Ghanem teaches that eosinophilia and proteinuria are seen in CCE subjects with impaired renal function and that CCE is marked by mainly dermal manifestations or elevation in serum creatinine (i.e hematologic abnormality). It would be obvious that in improving cholesterol crystal clearance and load in subjects with CCE that the symptoms associated with CCE would improve.
With respect to claim limitations regarding reduction in crystal size or reduction in crystal amount by “at least 10%”, the teaching of Zimmer that cholesterol crystal dissolution is increased and load/size is reduced by up to 50%, renders the dependent claim limitations obvious.
With respect to claims 44 and the limitation regarding levels of ABCA1 or ABCG1, this limitation is not accorded patentable weight because of the inseparable connection between an administered composition and the mechanism of action within the subject to which the composition is administered. The active method step in the instant claim is administering the HP-b-CD composition whereas the in vivo levels of ABCA1 or ABCG1 is an effect which will necessarily occur and does not delineate a manipulative difference between the instant method and the method of the prior art. Therefore, because the combined prior art teaches the same active step to administer the same composition, the properties applicant discloses and/or claims are necessarily present. Ex parte Novitski, 26 USPQ2d 1389 (Bd. Pat. App. & Inter. 1993). See also MPEP § 2112.02.
Accordingly, the instant claims are prima facie obvious over the teachings of the prior art.
Claims 8 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Zimmer et al. (Sci. Trans. Med., 2016, IDS), in view of Ghanem et al. (J. Biomed. Res., 2017, PTO-892), further in view of Meyrier (Kidney Inter., 2006, PTO-892).
The disclosure of Zimmer/Ghanem is referenced as discussed above. The combined prior art does not teach complement level as a diagnostic of CCE.
Meyrier discloses that CCE induces a form of anti-neutrophil cytoplasmic antibody negative angiitis, accompanied by clinical and laboratory features of inflammation: rapid erythrocyte sedimentation rate high C reactive protein levels, high eosinophil blood counts, and much more rarely hypocomplementemia, which is defined as a syndrome characterized by low levels of complement components C1, C4, and C3, often associated with conditions such as chronic recurrent urticaria and detectable anti-C1q autoantibodies. (p. 1310)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that in addition to the symptoms of eosinophilia, dermal manifestations, elevation in serum creatinine, etc., taught by Ghanem that abnormal complement level would be a further symptom of CEE, as per the teaching of Meyrier. It would be obvious that in improving cholesterol crystal clearance and load in subjects with CCE that the symptoms associated with CCE, such as complement level abnormalities, would improve.
Accordingly, the instant claims are prima facie obvious over the teachings of the prior art.
Claims 36 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Zimmer et al. (Sci. Trans. Med., 2016, IDS), in view of Ghanem et al. (J. Biomed. Res., 2017, PTO-892), further in view of Fornoni et al. (US 2019/0262385A1, IDS).
The disclosure of Zimmer/Ghanem is referenced as discussed above. The combined prior art does not teach the claimed dosing regimen.
Fornoni discloses a method for administering HP-b-CD to sequester cholesterol where the dosing regimen is as follows: (Claims 1, 2, 7, 10, 11) Dosage ranges for administering a compound in accordance with a method of the subject invention comprise from about 2-20 mg/kg/day to about 4000 mg/kg three to five times per week (totaling up to about 20,000 mg/kg/week), and can be administered at least two times per week up to about three times per day. (¶0026) Hydroxypropyl Beta Cyclodextrin (HPbCD) is safe when administered to mice at a dose ranging from about 2 to about 20 mg/kg/day and can be administered in amounts up to about 4,000 mg/kg from three times to five times per week (totaling about 20,000 mg/kg/week). (¶0067) After establishing a dose and a mode of administration based on preliminary toxicology studies, we treated 4-week old BTBR mice with subcutaneous administration of three weekly injections of hydroxypropyl-b-cyclodextrin (CD, 4,000 mg/kg body weight) for five months. (¶0101) The formulation may be such that an application, administration, or injection is required on a daily, weekly, monthly or other periodic basis, depending on the concentration and amount of a provided compound, the biodegradation rate of a polymer used in the formulation, and other factors known to those of skill in the art. (¶0060)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the dosing regimen in the method of Zimmer/Ghanem based on the disclosure of the analogous art of Fornoni. The dosing regimen of Fornoni renders obvious the claimed limitations of administering a first dose at one time point (e.g. upon first diagnosis, 3X-5X per week) and then administering a second dose at a second later time point (e.g. up to five months post first diagnosis).
Accordingly, the instant claims are prima facie obvious over the teachings of the prior art.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DALE R MILLER whose telephone number is (571) 272-6146. The examiner can normally be reached on M-F 7:00 AM – 3:30 PM EST.
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/DALE R MILLER/Primary Examiner, Art Unit 1693