1Notice 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
This Office Action is in response to Applicants’ Amendment and Remarks filed on 2/19/2026 in which claims 11-16, 26 and 31 are cancelled, claims 1, 21, 23, 24 and 35 are amended and claims 51-58 are newly added.
Claims 1, 4-7, 9, 10, 21, 23, 24, 35, 36 and 51-58 are pending in the instant application and are examined on the merits herein.
Priority
The application is a National Stage entry of PCT/US2021/048075 filed on 8/27/2021, which claims priority to provisional application 63/071243 filed on 8/27/2020.
Information Disclosure Statement
The information disclosure statements (IDS) dated 2/19/2026 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.
Withdrawn Rejections
All rejection(s) of record for claim(s) 11-16, 26 and 31 is/are hereby withdrawn due to the cancellation of said claim(s) rendering said rejection(s) moot.
Applicant’s amendment, filed on 2/19/2026, with respect to the rejection of claims 1, 4-7, 9, 10, 21, 23 and 24 under 35 U.S.C. 103 as being unpatentable over Zimmer et al. (Sci. Trans. Med., 2016), in view of Ghanem et al. (J. Biomed. Res., 2017), and claims 35, 36 under 35 U.S.C. 103 as being unpatentable over Zimmer et al. (Sci. Trans. Med., 2016), in view of Ghanem et al. (J. Biomed. Res., 2017), further in view of Fornoni et al. (US 2019/0262385A1), has been fully considered and is persuasive. Zimmer/Ghanem does not teach administering to humans at a dose of 50-2000 mg/kg. Fornoni does not remedy the deficiency of Zimmer/Ghanem. The rejections are hereby withdrawn.
Rejections Necessitated by Amendment
The following are new ground(s) or modified rejections necessitated by Applicants' amendment, filed on 2/19/2026, wherein instant independent claim 1 is amended and claims 51-58 are newly added. Therefore, new rejections are made.
New Rejections
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, 4-7, 9, 10, 21, 23, 24, 51-54 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Zimmer et al. (Sci. Trans. Med., 2016, IDS), with Zimmer et al. (Sci. Trans. Med., 2016, Supplementary Materials, PTO-892), in view of Ghanem et al. (J. Biomed. Res., 2017, reference of record).
Zimmer et al. discloses a method for treating atherosclerosis in mice and in human carotid plaques, by reducing plaque size and cholesterol crystal load, by administering 2-hydroxypropyl-beta-cyclodextrin (HP-b-CD), at a dose of 2 g/kg in mice. (Abstract, Figures 2 and 6-8) 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) and “CD, on the other hand, is already in clinical use in humans for the delivery of lipophilic drugs and has not shown relevant toxicity. Hence, repurposing CD for the treatment or prevention of atherosclerosis would be feasible. Our studies provide a proof of principle that therapies aimed at increasing the solubility and removal of macrophage cholesterol could be an effective strategy for the treatment of atherosclerosis.” (p. 9, Col. 2) Zimmer further discloses that human subjects with Niemann-Pick type C were intravenously administered HP-b-CD and it was observed that cholesterol content in the urine increased during HP-b-CD administration indicating that HP-b-CD enhances in vivo reverse cholesterol transport and can directly extract and transport cholesterol for excretion. (Figure 6D)
Zimmer et al. (Supplementary Materials) discloses that human subjects with Niemann-Pick type C were intravenously administered HP-b-CD at 2000 mg/kg. (p. 9)
Zimmer does not teach reducing the risk of or preventing 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…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)
It would have been 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, thereby arriving at the instant invention. 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 claim 24 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.
With respect to claim 51, it would be obvious to treat a subject with HP-b-CD, to reduce the cholesterol crystal load, prior to major cardiovascular surgery (i.e. “vascular or cardiovascular trauma”), because Ghanem teaches that CCE increases in likelihood during or after major cardiovascular surgery.
With respect to claim 52, it would have been obvious to one of ordinary skill in the art 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).
With respect to claims 53 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.
Accordingly, the instant claims are prima facie obvious over the teachings of the prior art.
Response to Arguments
As applicable to the new rejections, Applicants’ response with respect to the prior art of Zimmer/Ghanem has been fully considered but is not persuasive.
Applicant argues that the mouse data in Zimmer would not lead one of ordinary skill to treat a human, at the claimed dosage, with a reasonable assurance of success. Applicant argues that the 2 g/kg dose of Zimmer is for mice and is not applicable to humans. Applicants’ argument is not persuasive because Zimmer is not only directed to treatments in mice. Zimmer discloses successful reduction of cholesterol crystal load in plaques, biopsied from human subjects, further Zimmer (Supp. Mater.) shows that administering HP-b-CD, at 2000 mg/kg, is effective to increase cholesterol clearance in human subjects. Thus, Zimmer shows successful administration of HP-b-CD, within the claimed range, in both ex vivo and in vivo human systems. Given the data of Zimmer, when taken as a whole, POSITA would have a reasonable assurance of success in administering HP-b-CD, at 2000 mg/kg, to human patients, to treat atherosclerosis by reducing cholesterol crystal load. In view of Ghanem, it would then be further obvious that the method of Zimmer could be applied to treat subjects known to be at risk of CCE, which include subjects having atherosclerosis.
Applicant further argues that the data in the specification demonstrates unexpected success in enhancing cholesterol dissolution capacity when human subject was administered HP-b-CD at 500-1000 mg/kg. It is acknowledged that the data in Figures 1A and 2C shows the effectiveness of HP-b-CD from 500-1000 mg/kg at impacting the amount of free cholesterol, and its metabolites, in blood plasma of a human atherosclerotic patient. However, this data is not unexpected in view of Zimmer. There is no comparative data showing that a dose of 500-1000 mg/kg is unexpectedly different than the 2000 mg/kg dose administered to humans by Zimmer. Applicant is requested to note that it is well-settled that the evidence including a comparison with the closest prior art is one of elements to be considered as unexpected results (see for example, In re Merchant, 575 F.2d 865, 869, 197 USPQ 785, 788 (CCPA 1978), which is provided either in the specification or an affidavit or declaration submitted during prosecution on the issue.
The rejection is still deemed proper and is maintained.
Claims 35, 36 and 55-57 are rejected under 35 U.S.C. 103 as being unpatentable over Zimmer et al. (Sci. Trans. Med., 2016, IDS), with Zimmer et al. (Sci. Trans. Med., 2016, Supplementary Materials, PTO-892), in view of Ghanem et al. (J. Biomed. Res., 2017, reference of record), 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 or a dose from 250-1000 mg/kg.
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 (HP-b-CD) 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 and dosing regimen in the method of Zimmer/Ghanem based on the disclosure of the analogous art of Fornoni.
With respect to the dosing at 50-2000 mg/kg, 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); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). (MPEP § 2144.05(I)) Moreover, 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). (MPEP § 2144.05(II)) “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003).
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.
Response to Arguments
Applicant argues that the combined prior art does not render the independent claims prima facie obvious for the reasons outlined above, thus the rejection of dependent claims that reply on the teachings of said combined prior art, should be withdrawn. Applicants' arguments are not persuasive because the rejection of the independent claims is maintained as prima facie obvious over said combined prior art, as per the response to arguments above.
The rejection is still deemed proper and is maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new and/or modified ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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