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
Applicant’s amendment of 18 May 2026, in which claims 1, 2, 4, 5 have been amended, is acknowledged.
Claims 1-14, 17, 22, 28-31 are pending in the instant application.
Claims 1-14, 17, 22, 28-31 are being examined herein.
Response to arguments of 18 May 2026
In view of Applicant’s amendment, the objection to claim 1 is herein withdrawn.
Applicant’s arguments (Remarks of 18 May 2026, pages 6-9) against the rejection of claims 1-14, 17, 22, 28-31 under 35 U.S.C. 103 over Li, in view of Nair, have been considered.
Applicant argues that the combination of Li and Nair fails to render the claimed human dosage range obvious.
Applicant argues that the Office relies on Nair's teaching to calculate a Human Equivalent Dose (HED) of 533 mg based on Li's 16 mg/kg dog dose; however, the asserted calculation stops prematurely and disregards Nair's explicit guidance on clinically safe dosing.
Applicant argues that Nair provides a strict five-step procedure for determining a safe initial human dose (see, e.g., Figure 1 and the paragraph right above Figure 1). Step 4 of Nair's methodology explicitly requires that the HED must be divided by a safety factor (typically 10) to account for differences in physiological and biological processes between humans and animals to determine the safe starting dose. Applicant argues that if one were to actually follow Nair's teachings to convert Li's 533-666 mg HED into a safe human starting dose, Nair teaches dividing 533-666 mg HED by 10, resulting in a safe starting dose of approximately 53.3-66.7 mg. The pending claims have been amended to recite a dosing range of "about 100 mg to about 450 mg" per administration. Therefore, the prior art does not teach or render obvious the presently claimed dosing range.
In response, the examiner acknowledges Nair page 28 and Figure 1, and Applicant’s argument about the protocol /guidance by FDA where the NOAEL (no observed adverse effect levels) of drug from preclinical toxicological studies is scaled by making use of allometry to derive the maximum recommended starting dose MRSD for clinical studies (page 28, left column, examples calculations in right column); the protocol includes dividing HED by a factor of 10, to increase safety of first human dose, as Applicant argues. However, prior art by Chen does not teach the NOAEL in preclinical toxicological studies with the instant formulation of a compound of formula (I) and a cyclodextrin. Rather, Chen teaches administering such formulation of a compound of formula (I) and a cyclodextrin to animals (beagle dogs) at a dose of 20 mg/kg as part of PK studies (Example 11), which included determining oral bioavailability. As such, the dose used, 20 mg/kg, was a therapeutic dose, which is lower than the NOEAL.
To apply Nair’s calculations (page 28, right column) of initial dose in entry into human clinical studies, which are based on animal NOEAL (which include HED divided by a factor of 10), a dose higher than 20 mg/kg is to be used. NOEAL is the maximum dose of drug administered to animals with no observed adverse effect, and is determined experimentally across several animal species, as part of preclinical toxicity studies.
Applicant’s argument that it would not be a matter of routine optimization for a person of ordinary skill in the art to scale up from approximately 53.3-66.7 mg to a range of about 100 mg to about 450 mg, without risking severe adverse effects, is not persuasive, at least because the calculation presented by Applicant is based on an animal dose (20 mg/kg) lower than NOEAL.
Further, the question to ask is whether determining the starting dose to be used safely in human clinical trials, using a known formulation of a known drug, is unobvious. The examiner’s position is that estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult volunteers, using a known formulation of a known drug, is done under FDA guidance and follows well established protocol, and therefore is routine, well within the skill of the artisan, and a mandatory step in any clinical trial. As Nair explains, there is a process (algorithm) for deriving the maximum recommended starting dose (MRSD) for first-in-human clinical trials of new molecular entities in adult healthy volunteers, and a standardized process by which the MRSD can be selected. It is clear that the purpose of this process is to ensure the safety of the human volunteers. This protocol, as explained by Nair, uses common conversion factors for deriving a human equivalent dose (HED), based on animal dose.
Applicant has followed the steps within the FDA guidance to determine the starting dose to be used safely in human clinical trials, using a known formulation of a known drug.
In response to Applicant’s argument that it would not be a matter of routine optimization to arrive at 100 mg to 450 mg, the examiner notes that the HED calculation in mg/kg corresponds at different dose in mg, based on the weight of the human subject.
Applicant argues unexpected results.
a) The claimed 100-450 mg dose range has advantages/benefits over the 53.3-66.7 mg dose calculated from the prior art.
Applicant cites Example 1 of the present application, where AUC increased in a more-than- dose proportional manner in the range of 50-100 mg (which encompasses the 53.3-66.7 mg dose calculated from the prior art), while dose-proportionality was found in the range of 100-450 mg. This distinct shift brings several significant benefits in clinical practice, as elucidated below:
- Predictable Dose Titration;
- Dose-Independent Clearance and Distribution for the dose administered over the 100 to 350 mg range;
- Reduced Inter-Subject Variability
b) The claimed method achieved unexpected breaking of exposure saturation.
When the ASD-in-capsule formulation was used, the exposure increased in a linear, dose-proportional manner in the 100-450 mg range, achieving a massive AUC of 26,000 ng.h/mL at 450 mg-a nearly 30-fold increase compared to the API formulation at equivalent doses. See Conclusions of the present application at pages 24-25; while, when the API- in-capsule dose was increased from 400 mg to 800 mg, the systemic exposure (AUCO-inf) actually decreased from 1480 ng.h/mL to 935 ng.h/mL (“exposure saturation” Table 3 and Figures 2 and 3).
Applicant argues that the prior art provides no indication that the ADS-in-capsule formulation in the 100-450 mg range would allow clinicians to safely bypass the drug's inherent absorption limits in humans.
In response, determining the dose in mg per administration of a known formulation of a known drug, to be administered safely to a human patient, based on a 20 mg/kg animal dose, is routine, well within the skill of the artisan. Further, Chen teaches the very formulation as in the instant invention, which is a formulation of compound of formula (I) in cyclodextrin. Chen also teaches [0038] 150 mg compound + 450 mg HPBCD physical mixture, which is a composition comprising 150 mg of compound (I), which is within the instant range. That is why a comparison with API in capsule (no cyclodextrin) does not constitute unexpected results, because it is not a comparison with the closest prior art (Chen).
Applicant argues that the PK parameters are not inherent because the prior art does not teach or render obvious the administration of the composition in the range of 100-450 mg.
The examiner maintains that Li teaches orally administering to dogs a dose of 20 mg/kg or 16 mg/kg of a IVO/HPBCD composition, which is the very composition in the instant claims; calculating the equivalent dose of said composition to be administered to a human subject, is routine, well within the skill of the artisan. The PK parameters are a result of administering to a human subject the dose of compound (I) in a formulation with cyclodextrin. The examiner notes that the properties of the composition are inherent to the composition. Therefore, if the prior art teaches the composition or renders the composition obvious, then the PK properties are also taught or rendered obvious by the prior art.
For these reasons, the rejection is herein maintained.
Applicant traverses (Remarks of 18 May 2026, page 9, last paragraph- page 10) the rejections of the instant claims on the ground of nonstatutory double patenting over claims of copending U.S. Patent Application No. 18/568,031; over claims of U.S. Patent 10,532,102, in view of Li, in further view of Nair; over claims of U.S. Patent 11,013,810, in view of Li, in further view of Nair; over claims of U.S. Patent 11,628,220, in view of Li, in further view of Nair, using the same arguments as above. For the same reasons as presented above, these rejections are herein maintained.
Applicant’s amendment of 18 May 2026 necessitated the following modified 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, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim interpretation: the term “safely administering” in claim 1, based on the teaching in the Specification, page 27, is consistent with safety of administration being assessed at pre-specified timepoints throughout the studies by AEs reporting, vital signs measurements, physical examination, laboratory tests, and ECG examinations. All recorded AEs were self-limited and considered to be of mild intensity. No severe or serious AEs were reported (page 24, 32). There were only few AEs that were mild, short-lasting, and self-limited; there was no increase in frequency or intensity of AEs at higher dose levels (page 32). None of the subjects discontinued from the study due to an AE. No clinically relevant changes from baseline assessments were observed in weight, vital signs, physical examination, laboratory or ECG data after the administration of the compound of formula (I) at any time point.
Claims 1-14, 17, 22, 28-31 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (US 2019/0054178, published 21 February 2019, cited in PTO-892 of 19 February 2026), in view of Nair et al. (Journal of Basic and Clinical Pharmacy 2016, 7 (2), 27-31, cited in PTO-892 of 19 February 2026).
Li (US 2019/0054178) teaches [0020] a method of administering a pharmaceutical composition containing a compound of the formula (I)
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and a cyclodextrin to an animal or human subject.
Li specifically teaches [0030] IVO: 5-{3-[4-(3-Methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidine-2,4-dione as a compound of formula (I), which the very compound of the instant claims.
Thus, Li teaches a method of administering to a human subject a pharmaceutical composition containing a compound of the instant claims 5-{3-[4-(3-Methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidine-2,4-dione (IVO) and a cyclodextrin.
Li studies (Example 4) the effect of different cyclodextrins on the aqueous solubility of 5-{3-[4-(3-Methyl-benzyloxy)phenylthio]-fur-2-yl}-imidazolidin-2,4-dione (IVO)
[0035]. Li teaches ([0035], Table 4) that the enhancement effect on the aqueous solubility of compound IVO is in the order of MBCD>SBEBCD>HPBCD>HPGCD>ACD. MBCD (methyl beta cyclodextrin) is the most effective solubility improving agent in this experiment.
Li prepares ([0037], Example 6, Table 6) a complex of compound IVO, which is the very compound of the instant claims, with hydroxypropyl beta-cyclodextrin HPBCD, as in instant claim 30, where the weight ratio of the compound to the cyclodextrin is 1:3 (IVO:HPBCD = 25 : 75 (w/w)), which is within the range in instant claim 31. The IVO/HPBCD complex is named IVO/HPBCD ASD-01 [0037].
The composition comprises the compound of the instant claims, as in instant claim 28, and is amorphous [0037].
Li teaches [0004] that the compounds of the invention are selective inhibitors of MMP-12 useful in the treatment of diseases or conditions mediated by MMP-12, such as asthma, or chronic obstructive pulmonary diseases (COPD), as in instant claim 22.
Li prepares [0038] a unit dose comprising 150 mg IVO + 450 mg HPBCD, which is a composition comprising a cyclodextrin and 150 mg of the compound of the instant claims, where the unit dose is as in instant claims 2, 4, and is within the range in instant claim 1.
Li teaches (Example 11) a method of orally administering to a subject which is a beagle dog a pharmaceutical composition (suspension) comprising hydroxypropyl-β-cyclodextrin (HPBCD) and IVO (which is the compound of the instant claims), wherein the dose of the compound IVO administered is 20 mg/kg [0049], [0051].
Li analyzes (Example 11) plasma samples [0063] collected from animals upon administration once a day, as in instant claims 3, 9-14, and determines PK parameters [0066], Table 12, namely the observed maximum plasma concentration (Cmax), as in instant claim 10, and the time of Cmax (Tmax), as in instant claim 12; the area under the plasma concentration-time curve from time-0 to 24 hour post-dose (AUC0-24 h) and the area under the plasma concentration-time curve from time-0 extrapolated to infinity (AUC 0-∞), as in instant claim 9; the apparent terminal elimination half-life (T1/2) [0068], as in instant claim 11; the total clearance [0069], as in instant claim 13; and the volume of distribution [0069], as in instant claim 14.
Li teaches (Example 12) a method of orally administering to a subject which is a beagle dog a pharmaceutical composition (capsule) comprising hydroxypropyl-β-cyclodextrin (HPBCD) and IVO (which is the compound of the instant claims) (composition called IVO ADSD-01), wherein the dose of the compound IVO administered is 150 mg/dog (Table, [0099]), corresponding to 16 mg/kg dog (Table 15).
Li analyzes (Table 15) plasma samples collected from animals upon administration once a day, as in instant claims 3, 9-14, and determines PK parameters, Table 15, namely the observed maximum plasma concentration (Cmax), as in instant claim 10, and the time of Cmax (Tmax), as in instant claim 12; the area under the plasma concentration-time curve from time-0 to 24 hour post-dose (AUC0-24 h) and the area under the plasma concentration-time curve from time-0 extrapolated to infinity (AUC 0-∞), as in instant claim 9.
Li [0130]-[0131] evaluates the safety of the administration by clinical observation of the animals for mortality and signs of pain and distress; cage-side observations for general health and appearance were made once daily; on the dosing day, the animals were observed before and after each blood collection time point, with any unusual observations noted throughout the duration of the study being recorded in the study folder.
Li is silent regarding serious adverse effects and clinically significant changes in the subjects upon administration, which satisfies the limitation of claims 6-8.
Li does not teach administering the composition twice day, as in instant claims 3-5, 9-14, 17. Li does not multiple day administration, to achieve steady state, as in instant claim 17.
While Li teaches orally administering to dogs a dose of 20 mg/kg or 16 mg/kg of a IVO/HPBCD composition, Li does not specifically teach that the oral dose administered to a human subject is 100 mg to 450 mg, as in instant claims.
Nair et al. (Journal of Basic and Clinical Pharmacy 2016, 7 (2), 27-31) teach dose calculations to convert doses between animals and humans (Table 1, Table 2, page 29).
Since Li teaches (Table 15) that a composition IVO/HPBCD is administered orally to dogs at a dose of 20 mg/kg, or at 16 mg/kg, using the teachings in Nair,
the corresponding dose in mg/kg for humans is calculated as follows:
20 mg/kg dog / 1.8 = 11.1 mg/kg HED,
which, for a human patient weighing 40 kg, corresponds to 444 mg;
or, for 16 mg/kg dog, the corresponding dose in mg/kg for humans is calculated as follows:
16 mg/kg dog / 1.8 = 8.8 mg/kg HED,
which, for a human patient weighing 40 kg, corresponds to 352 mg, which is within the range in instant claims 1, 2, 4, 5.
It would have been obvious to a person of ordinary skill in the art to use the teachings of Li and Nair to arrive at the instantly claimed method. The person of ordinary skill in the art would have been motivated to orally administer to a human subject a pharmaceutical composition taught by Li containing 5-{3-[4-(3-Methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidine-2,4-dione (IVO) and hydroxypropyl beta-cyclodextrin, and determine the human equivalent dose corresponding to the dose administered to dogs (Li), because calculating the human equivalent dose (HED) based on the animal dose, in a method of administering a therapeutic agent, is routine, well within the skill of the artisan.
Thus, the person of ordinary skill in the art would have converted the dose taught by Li into a human equivalent daily dose in mg, and would have administered said dose or a lower dose to a human subject using daily administration, or twice a day administration, for several days, with monitoring for PK parameters and side effects, because such a protocol for determining the dose for safety administration of a therapeutic agent to humans is routine, well within the skill of the artisan, and a required part of any clinical trial.
With respect to the PK limitations in claim 9-14, 17, the properties of the composition are inherent to the composition. Therefore, if the prior art teaches the composition or renders the composition obvious, then the properties are also taught or rendered obvious by the prior art. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990.) See MPEP 2112.01. The burden is shifted to Applicant to show that the prior art product does not possess or render obvious the same properties as the instantly claimed product.
With respect to the limitation in instant claims 9-14, 17, even though Li does not specifically teach the AUC or Cmax levels (or other PK parameters listed in claims 9-14, 17) achieved in the human patient upon administration of the composition comprising 5-{3-[4-(3-Methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidine-2,4-dione (IVO) and cyclodextrin, the ability to achieve said AUC or Cmax of IVO levels in a human patient upon administration is an inherent property of the IVO/cyclodextrin composition. In the instant case, achieving the claimed AUC and Cmax levels is inherently associated with administering a composition comprising IVO and cyclodextrin.
As such, claims 1-14, 17, 22, 28-31 are rejected as prima facie obvious.
Double patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-14, 17, 22, 28-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable at least over claims 1-11 of copending U.S. Patent Application No. 18/568,031 (published as US 20240269116, cited in PTO-892 of 19 February 2026). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-11 of copending U.S. Patent Application No. 18/568,031 render obvious the instant claims.
Claims 1-11 of copending U.S. Patent Application No. 18/568,031 are drawn to a method of treating acute respiratory distress syndrome (ARDS) in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition in a therapeutically effective amount, wherein the pharmaceutical composition comprises a cyclodextrin and a compound of formula (F-I)
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Thus, claims 1-11 of copending U.S. Patent Application No. 18/568,031 recite administering (safely, since said step is part of a method of treatment) to a subject the very composition as in the instant claims, namely a composition comprising the compound of the instant claims, and a cyclodextrin. The genus of subjects in claims 1-11 of copending U.S. Patent Application No. 18/568,031 include human subjects, which is the patient population in the instant claims. Claims 2, 4, 5, 6 of copending U.S. Patent Application No. 18/568,031 recite a total dosage of the compound of formula (F-I) administered per administration is about 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, or 500 mg, or any dosage in between, which overlaps with the dose in instant claims 1, 2, 4, 5; claim 3 of copending U.S. Patent Application No. 18/568,031 recites that the pharmaceutical composition is administered once or twice per day, as in instant claims 3-5, 9-14, 17. Claim 7 of copending U.S. Patent Application No. 18/568,031 recites oral administration, as in the instant claims; claim 8 recites that the pharmaceutical composition comprises the compound of formula (F-I), as in instant claim 28; claim 9 recites that
the cyclodextrin is a hydroxypropyl beta-cyclodextrin (HPBCD), as in instant claim 30; claim 10 recites that the molar ratio of the compound of formula (F-I) to the cyclodextrin is from 1:0.1 to 1:10, as in instant claim 31.
It would have been obvious to a person of ordinary skill in the art to orally administer to a human subject the composition comprising compound F1 and a cyclodextrin of claims 1-11 of copending U.S. Patent Application No. 18/568,031, at the same or overlapping dose, to arrive at the instant invention. With respect to the limitation in instant claims 9-14, 17, even though claims 1-11 of copending U.S. Patent Application No. 18/568,031 do not specifically teach the AUC or Cmax levels (or other PK parameters listed in claims 9-14, 17) achieved in the human patient upon administration of the composition comprising 5-{3-[4-(3-Methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidine-2,4-dione and cyclodextrin, the ability to achieve said AUC or Cmax of IVO levels in a human patient upon administration is an inherent property of the IVO/cyclodextrin composition. In the instant case, achieving the claimed AUC and Cmax levels is inherently associated with administering a composition comprising IVO and cyclodextrin.
This is a provisional nonstatutory double patenting rejection.
Claims 1-14, 17, 22, 28-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent 10,532,102 (cited in PTO-892 of 19 February 2026), in view of Li et al. (US 2019/0054178, published 21 February 2019, cited in PTO-892 of 19 February 2026), in further view of Nair et al. (Journal of Basic and Clinical Pharmacy 2016, 7 (2), 27-31, cited in PTO-892 of 19 February 2026). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-3 of U.S. Patent 10,532,102 render obvious the instant claims.
Claims 1-3 of U.S. Patent 10,532,102 are drawn to a pharmaceutical composition comprising a compound of 5-{3-[4-(3-Methyl-benzyloxy) phenylthio]fur-2-yl}imidazolidine-2,4-dione (IVO); and a cyclodextrin, wherein the cyclodextrin is hydroxypropyl beta-cyclodextrin (as in instant claim 30), which is the very composition in the instant claims. Claim 2 of U.S. Patent 10,532,102 recites that the weight ratio of the compound of formula (I) to the cyclodextrin is 1:3, which is within the range in instant claim 31.
The Specification of U.S. Patent 10,532,102 teaches (column 2, lines 22-25) a method of administering a composition of the invention to a human subject.
Li teaches a method of administering orally a pharmaceutical composition comprising a compound of 5-{3-[4-(3-Methyl-benzyloxy) phenylthio]fur-2-yl}imidazolidine-2,4-dione (IVO); and a cyclodextrin, to dogs at a dose of 20 mg/kg, or 16 mg/kg, with monitoring of PK parameters and adverse effects.
Nair are as above.
It would have been obvious to a person of ordinary skill in the art to combine the teachings of claims 1-3 of U.S. Patent 10,532,102, Li and Nair to arrive at the instantly claimed method. The person of ordinary skill in the art would have been motivated to orally administer to a human subject a pharmaceutical composition taught by claims 1-3 of U.S. Patent 10,532,102, and determine the human equivalent dose corresponding to the dose administered to dogs (Li), because calculating the human equivalent dose (HED) based on the animal dose, in a method of administering a therapeutic agent, is routine, well within the skill of the artisan.
Thus, the person of ordinary skill in the art would have converted the dose taught by Li into a human equivalent daily dose in mg, and would have administered said dose or a lower dose to a human subject using daily administration, or twice a day administration, for several days, with monitoring for PK parameters and side effects, because such a protocol for determining the dose for safety administration of a therapeutic agent to humans is routine, well within the skill of the artisan, and a required part of any clinical trial.
With respect to the PK limitations in claim 9-14, 17, the properties of the composition are inherent to the composition. Therefore, if the prior art teaches the composition or renders the composition obvious, then the properties are also taught or rendered obvious by the prior art. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990.) See MPEP 2112.01. The burden is shifted to Applicant to show that the prior art product does not possess or render obvious the same properties as the instantly claimed product.
With respect to the limitation in instant claims 9-14, 17, even though prior art does not specifically teach the AUC or Cmax levels (or other PK parameters listed in claims 9-14, 17) achieved in the human patient upon administration of the composition comprising 5-{3-[4-(3-Methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidine-2,4-dione (IVO) and cyclodextrin, the ability to achieve said AUC or Cmax of IVO levels in a human patient upon administration is an inherent property of the IVO/cyclodextrin composition. In the instant case, achieving the claimed AUC and Cmax levels is inherently associated with administering a composition comprising IVO and cyclodextrin.
As such, claims 1-14, 17, 22, 28-31 are rejected as prima facie obvious.
Claims 1-14, 17, 22, 28-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent 11,013,810 (cited in PTO-892 of 19 February 2026), in view of Li et al. (US 2019/0054178, published 21 February 2019, cited in PTO-892 of 19 February 2026), in further view of Nair et al. (Journal of Basic and Clinical Pharmacy 2016, 7 (2), 27-31, cited in PTO-892 of 19 February 2026). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-21 of U.S. Patent 11,013,810 render obvious the instant claims.
Claims 1-21 of U.S. Patent 11,013,810 are drawn to a pharmaceutical composition comprising a compound of formula I
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and a cyclodextrin, wherein R is, for example, 3-methylphenyl, and wherein (claims 4, 5) the cyclodextrin is hydroxypropyl beta-cyclodextrin (as in instant claim 30), which is the very composition in the instant claims. Claims 2, 8 of U.S. Patent 11,013,810 recites that the weight ratio of the compound of formula (I) to the cyclodextrin is 1:1 to 1:50, which overlaps with the range in instant claim 31. Claims 14, 18 of U.S. Patent 11,013,810 recite a pharmaceutical composition comprising a cyclodextrin and a compound of formula (I) which is 5-{3-[4-(3-Methyl-benzyloxy) phenylthio]fur-2-yl}imidazolidine-2,4-dione, which is the very compound of the instant claims.
Claims 16, 20, 21 of U.S. Patent 11,013,810 recite Cmax and oral bioavailability which are achieved upon administration of the composition.
The Specification of U.S. Patent 11,013,810 teaches (column 2, lines 22-25) a method of administering a composition of the invention to a human subject.
Li teaches a method of administering orally a pharmaceutical composition comprising a compound of 5-{3-[4-(3-Methyl-benzyloxy) phenylthio]fur-2-yl}imidazolidine-2,4-dione and a cyclodextrin, to dogs at a dose of 20 mg/kg, or 16 mg/kg, with monitoring of PK parameters and adverse effects.
Nair is as above.
It would have been obvious to a person of ordinary skill in the art to combine the teachings of claims 1-21 of U.S. Patent 11,013,810, Li and Nair to arrive at the instantly claimed method. The person of ordinary skill in the art would have been motivated to orally administer to a human subject a pharmaceutical composition taught by claims 1-21 of U.S. Patent 11,013,810, and determine the human equivalent dose corresponding to the dose administered to dogs (Li), because calculating the human equivalent dose (HED) based on the animal dose, in a method of administering a therapeutic agent, is routine, well within the skill of the artisan.
Thus, the person of ordinary skill in the art would have converted the dose taught by Li into a human equivalent daily dose in mg, and would have administered said dose or a lower dose to a human subject using daily administration, or twice a day administration, for several days, with monitoring for PK parameters and side effects, because such a protocol for determining the dose for safety administration of a therapeutic agent to humans is routine, well within the skill of the artisan, and a required part of any clinical trial.
With respect to the PK limitations in claim 9-14, 17, the properties of the composition are inherent to the composition. Therefore, if the prior art teaches the composition or renders the composition obvious, then the properties are also taught or rendered obvious by the prior art. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990.) See MPEP 2112.01. The burden is shifted to Applicant to show that the prior art product does not possess or render obvious the same properties as the instantly claimed product.
With respect to the limitation in instant claims 9-14, 17, even though prior art does not specifically teach the AUC or Cmax levels (or other PK parameters listed in claims 9-14, 17) achieved in the human patient upon administration of the composition comprising 5-{3-[4-(3-Methyl-benzyloxy)phenylthio]fur-2-yl}imidazolidine-2,4-dione (IVO) and cyclodextrin, the ability to achieve said AUC or Cmax of IVO levels in a human patient upon administration is an inherent property of the IVO/cyclodextrin composition. In the instant case, achieving the claimed AUC and Cmax levels is inherently associated with administering a composition comprising IVO and cyclodextrin.
As such, claims 1-14, 17, 22, 28-31 are rejected as prima facie obvious.
For similar reasons as above, claims 1-14, 17, 22, 28-31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent 11,628,220 (cited in PTO-892 of 19 February 2026), in view of Li et al. (US 2019/0054178, published 21 February 2019, cited in PTO-892 of 19 February 2026), in further view of Nair et al. (Journal of Basic and Clinical Pharmacy 2016, 7 (2), 27-31, cited in PTO-892 of 19 February 2026).
Conclusion
Claims 1-14, 17, 22, 28-31 are rejected.
Applicant's amendment necessitated the new 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 nonprovisional extension fee (37 CFR 1.17(a)) 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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/IRINA NEAGU/Primary Examiner, Art Unit 1629
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