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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/10/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
Claims 1-2 and 7-11 are pending in this application. Claims 3-6 have been cancelled by Applicant.
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 1-2 and 7-11 are rejected under 35 U.S.C. 103 as being unpatentable over Tang et al. (J. Am. Chem. Soc. 2010, 132, 12150-12154) (“Tang”); in view of Twala et al. (Drugs targeting the Retinoblastoma binding protein, 2017 – From IDS – previously cited) (“Twala”); further in view of Murphy et al. (Expert Opinion On Drug Metabolism and Toxicol., 2015, 11:4, 589-599) (“Murphy”); further in view of Hou et al. (Cancer Cell Int., 2019, 19: 216, 8 pages – previously cited) (“Hou”).
Regarding claims 1-2 and 7-11, Tang discloses the fluorinated ezetimibe derivative 26 (resulting from the replacement of a -OH for -F) (instant Formula (I)) (Scheme 1, page 12153, col.1).
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While Tang does not specifically teach: (i) the instant modified ezetimibe compound in a method for treating a cancer wherein MDM2 is overexpressed, such as esophagogastric cancer and colorectal cancer (claim 1); or (ii) improved bioavailability, docking score, increased lipophilicity, etc. of the instant modified ezetimibe compound over ezetimibe (claims 7-11); the teachings of Twala, Murphy, and Hou are relied upon for these disclosures.
Twala studies RBBP6 with special focus in its p53 domain and the interaction with MDM2 (abstract). Using computational methods, Twala concludes that ezetimibe tightly binds into the MDM2 p53-binding domain (hydrophobic pocket) (page 48, para. 2, last 4 lines; and page 49, Figure 4.18) and suggests that, therefore, it will have significant impact in cancers with high MDM2 expression (page 48, para. 3, last 4 lines; and Fig. 4.18 A-D).
Murphy teaches fluorine’s unique physicochemical properties make it a key element for incorporation into pharmacologically active compounds (abstract). Murphy teaches fluorine has unique physicochemical properties and can be introduced into drug systems in place of H or OH
with minor steric, but potentially major electronic, consequences (article highlights box, col. 1, page 590). Introducing fluorine into an aromatic compound increases lipophilicity (section 2.3, page 591, col. 1). Murphy specifically teaches the purpose of fluorine incorporation into drug molecules is often to slow or prevent metabolic attack, by increasing resistance to CYP-mediated oxidation, thereby prolonging the pharmacological effects of the drug (section 2.6, page 592, col. 1). Murphy further states that the presence of fluorine in a drug can alter aspects such as receptor- and active-site binding, lipophilicity, bioavailability and metabolic stability. Improvement in a drug’s activity is often a combination of these factors (section 5, col. 1, page 596).
Hou discloses MDM2 overexpression can be detected in many malignancies like esophagogastric cancer and colorectal cancer (page 1, col. 2, para. 2, lines 8-11).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to treat a cancer in which MDM2 is overexpressed, such as esophagogastric cancer and colorectal cancer, by administering Tang’s modified ezetimibe compound, in view Twala, further in view of Murphy and Hou. One of ordinary skill would have been motivated to do so because Tang discloses their fluorinated derivative of ezetimibe; Twala’s disclosure that ezetimibe tightly binds into the hydrophobic pocket of MDM2 p53-binding domain; Murphy teaches that -F and -OH are known bioisosteres in medicinal chemistry, and that presence of fluorine in a drug can alter aspects such as receptor- and active-site binding, lipophilicity, bioavailability and metabolic stability; further because Hou discloses that MDM2 overexpression can be detected in many malignancies, like esophagogastric and colorectal cancer. One of ordinary skill would have had a reasonable expectation of success because Tang discloses conditions for synthesizing the fluorinated derivative of ezetimibe; Twala suggests that ezetimibe will have significant impact in cancers with high MDM2 expression; and because of Murphy’s teaching that fluorine in a drug can alter aspects such as receptor- and active-site binding, lipophilicity, bioavailability and metabolic stability.
Applicant is advised that similar properties may normally be presumed when compounds are very close in structure. Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Grabiak, 769 F.2d 729, 731, 226 USPQ 870, 871 (Fed. Cir. 1985) (“When chemical compounds have very close structural similarities and similar utilities, without more a prima facie case may be made.”). Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious. Dillon, 919 F.2d at 697-98, 16 USPQ2d at 1905; In re Wilder, 563 F.2d 457, 461, 195 USPQ 426, 430 (CCPA 1977); In re Linter, 458 F.2d 1013, 1016, 173 USPQ 560, 562 (CCPA 1972) (see MPEP 2144.08(d)).
Regarding claims 2 and 7-11, it is noted that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim. See MPEP 2103 I.C. and MPEP § 2111.04.
It is also noted that a “wherein” clause, such as that in claims 2 and 7-11, must give “meaning and purpose to the manipulative steps.” See, MPEP § 2111.04. Furthermore, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP § 2111.02.
Furthermore, Applicant is advised that products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Further regarding claims 2 and 9-10, Twala teaches ezetimibe tightly binds into the MDM2 p53-binding domain (a hydrophobic pocket) (page 48, para. 2, last 4 lines; and page 49, Figure 4.18). One of ordinary skill would have been motivated to with a reasonable expectation of success because replacing -OH with -F is expected to increase lipophilicity of a compound, thus resulting in tighter binding (or “higher docking score”) – as taught by Murphy – of Tang’s fluorinated compound 26 with Twala’s hydrophobic pocket.
Further regarding claims 7-8 and 11, Murphy teaches that fluorine in a drug can alter aspects such as receptor- and active-site binding, lipophilicity, bioavailability and metabolic stability. Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to expect improved/increased bioavailability relative to ezetimibe. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of the teachings above.
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 1-2 and 7-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31-33, 38-40, and 45-47 of copending Application No. 17/776,276 (Copending ‘276); in view of Tang et al. (J. Am. Chem. Soc. 2010, 132, 12150-12154) (“Tang”); in view of Murphy et al. (Expert Opinion On Drug Metabolism and Toxicol., 2015, 11:4, 589-599) (“Murphy”); further in view of Hou et al. (Cancer Cell Int., 2019, 19: 216, 8 pages – previously cited) (“Hou”).
Regarding instant claims 1-2 and 7, Copending ‘276 claims a method of treating cancer comprising oral administration of ezetimibe, wherein the cancer is characterized by overexpression of Mdm2, such as colon cancer (Copending ‘276’s claims 31-33).
While Copending ‘276 does not specifically claim: (i) the instant fluorinated ezetimibe (claim 1); (ii) the relationship between MDM2 and colorectal and esophagogastric cancers (claim 1); or (iii) improved bioavailability/lipophilicity/docking score of the instant modified ezetimibe over ezetimibe (claims 7-11); the teachings of Tang, Murphy, and Hou are relied upon for these disclosures.
Tang discloses the fluorinated ezetimibe derivative 26 (resulting from the replacement of a -OH for -F) (instant Formula (I)) (Scheme 1, page 12153, col.1).
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Murphy teaches fluorine’s unique physicochemical properties make it a key element for incorporation into pharmacologically active compounds (abstract). Murphy teaches fluorine has unique physicochemical properties and can be introduced into drug systems in place of H or OH
with minor steric, but potentially major electronic, consequences (article highlights box, col. 1, page 590). Introducing fluorine into an aromatic compound increases lipophilicity (section 2.3, page 591, col. 1). Murphy specifically teaches the purpose of fluorine incorporation into drug molecules is often to slow or prevent metabolic attack, by increasing resistance to CYP-mediated oxidation, thereby prolonging the pharmacological effects of the drug (section 2.6, page 592, col. 1). Murphy further states that the presence of fluorine in a drug can alter aspects such as receptor- and active-site binding, lipophilicity, bioavailability and metabolic stability. Improvement in a drug’s activity is often a combination of these factors (section 5, col. 1, page 596).
Hou discloses MDM2 overexpression can be detected in many malignancies like esophagogastric cancer and colorectal cancer (page 1, col. 2, para. 2, lines 8-11).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to treat a cancer in which MDM2 is overexpressed, such as esophagogastric cancer and colorectal cancer, by administering the instant modified ezetimibe compound, in view of Copending ‘276, further in view of Tang, Murphy, and Hou. One of ordinary skill would have been motivated to do so in view Copending ‘276’s suggestion that ezetimibe is an MDM2 inhibitor (since it can trat cancers characterized by overexpression of MDM2); Tang’s disclosure of their fluorinated ezetimibe derivative; Murphy’s teachings that -F and -OH are known bioisosteres in medicinal chemistry; and Hou’s disclosure that MDM2 overexpression can be detected in many malignancies, like esophagogastric and colorectal cancer. One of ordinary skill would have had a reasonable expectation of success in view of Copending ‘276’s disclosure of a method of treating cancers with high MDM2 expression by administering ezetimibe; Tang’s disclosure of conditions for synthesizing the instantly claimed fluorinated derivative of ezetimibe; and Murphy’s disclosure that the incorporation of fluorine in drug targets can productively modulate metabolic stability, lipophilicity, and bioavailability.
Applicant is reminded that similar properties may normally be presumed when compounds are very close in structure. (“When chemical compounds have very close structural similarities and similar utilities, without more a prima facie case may be made.”). Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious.
Regarding instant claims 2 and 7-11, Applicant is reminded that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim.
It is also noted that a “wherein” clause, such as that in claims 2 and 7-11, must give “meaning and purpose to the manipulative steps.”
Further regarding claims 2 and 9-10, Copending ‘276 teaches ezetimibe binds into the MDM2.
Further regarding claims 7-8 and 11, Murphy teaches that fluorine in a drug can alter aspects such as receptor- and active-site binding, lipophilicity, bioavailability and metabolic stability. Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to expect improved/increased bioavailability relative to ezetimibe. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of the teachings above.
Response to Arguments
Claims
Claim amendments are acknowledged. No new matter has been introduced.
Claim Rejections - 35 USC § 103
Applicant’s arguments with respect to instant claims have been considered but are moot because the new ground of rejection does not rely on the reference combination applied in the prior rejection of record.
Applicant argues a skilled person would not be motivated to modify orally administered ezetimibe for the treatment of cancers as an intravenous agent; that the instant compound is “expected to have different off-target interactions … not predicted to bind to the Nieman-Pick C1 like protein), and that therefore, the instant compound is unlikely to be useful for the treatment of cholesterol-like conditions and have a lower binding probability to cannabinoid receptor compared to ezetimibe.
In response to applicant's arguments above, that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that, as presented with the Annexure B filed 12/09/2025, the bioavailability of orally administered ezetimibe is much lower than the instant compound, citing Figures 2 and 4 from the Annexure, stating there is a surprising shift of the curve to the right, indicating the instant compound resists biotransformation in systemic circulation.
Firstly, Applicant is advised that the information submitted as a Miscellaneous Letter on 12/09/2025 is not persuasive. Examiner suggests submitting evidence of unexpected results as a declaration or affidavit for it to have any weight in the patentability argument.
Furthermore, in response, Applicant is advised that the “surprising resistance to biotransformation” is not surprising in view of the cited art. Murphy specifically discloses that the presence of fluorine in a drug can alter aspects such as receptor and active-site binding, lipophilicity, bioavailability and metabolic stability. Improvement in a drug’s activity is often a combination of these factors (section 5, col. 1, page 596) – see 103 rejections above. Therefore, this increase in bioavailability and metabolic stability is expected, as Murphy also states that the purpose of fluorine incorporation into drug molecules is often to slow or prevent metabolic attack, by increasing resistance to CYP-mediated oxidation, thereby prolonging the pharmacological effects of the drug (section 2.6, page 592, col. 1).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Double Patenting
Applicant’s arguments with respect to instant claims have been considered but are moot because the new ground of rejection does not rely on the reference combination applied in the prior rejection of record.
Applicant argues the claims are allowable in view of their arguments above. Therefore, for the reasons outlined above, claims stand rejected over provisional non-statutory double patenting over Copending ‘276, cited herein.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627