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 .
Priority
This application filed on 11/07/2023, is a U.S. National Stage Application, filed under 35 U.S.C. § 371, of International Application No. PCT/US2022/072194 filed on 05/09/2022, which claims priority to U.S. Provisional Application No. 63/185,921, filed on 05/07/2021.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 01/05/2024, complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits, except where noted.
Status of claims
The premilitary amendment filed on 08/09/2024, that amended claims 3-8, 10-15, 17-20, and 22-23, and cancelled claims 9, 16, 21, and 24-26, is acknowledged.
Claims 1-8, 10-15, 17-20, and 22-23 are pending.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-8, 13-15, 19-20, and 22-23 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by M. Weiss (US PG PUB 2023/0144292A1, 05/11/2023, “Weiss” cited in the IDS dated 01/05/2024).
Prior Art Effect of Weiss
The earliest possible effective filing date of the subject claims is that of priority document U.S. Provisional Application No. 63/185,921, filed on 05/07/2021. Weiss is effective prior art under 35 USC § 102(a)(2) respecting the subject matter cited in this rejection as of the filing date of Weiss priority document U.S. Provisional Application No. 62/949,298 filed on 12/17/2019 because: (1) Weiss is U.S. patent application publication; (2) names another inventor; and (3) the subject matter of Weiss relied upon in this rejection is disclosed in Weiss’s priority document U.S. Provisional Application No. 62/949,298 (12/17/2019). See MPEP § 2154.01; 35 USC § 102(d). Thus, the effective filing date of the subject matter relied upon in this rejection is 12/17/2019, which is before the claims’ earlies possible effective filing date of 05/07/2021. See MPEP § 2154.01; 35 USC § 102(d).
Joint Inventorship
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.
Weiss discloses bifunctional compounds of formula Ia, which function to recruit IRAK kinases to E3 Ubiquitin Ligase for degradation. [0009]. Weiss discloses compound I-3 below [page 159, [0263]]:
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Weiss’s compound I-3 anticipates claim 1 formula I wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R", R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, and R48 are H.
With regard to the claim 1 limitation “at least one of the above listed R1-48 is D”:
As well known in the art, hydrogen consists of three isotopes: (1) hydrogen or protium (P or H), (2) deuterium (D); and (3) tritium (T), with mass numbers 1, 2, and 3 respectively. The natural isotopic abundance of Hydrogen 1H is 99.985 % and that of 2H is 0.015 %. W. Meier-Augenstein et al., Stable Isotope Analysis: General Principles and Limitations, In Wiley Encyclopedia of Forensic Science, 1-15 (2012). Also, it is more common to find deuterium bonded to a protium atom to form hydrogen deuteride, which is written as HD or 1H2H.See A. M. Helmenstine, Deuterium Facts, 2019. Thus, deuterium is involved in every synthetic reaction in which hydrogen is employed.
Therefore, claims 1-8, 13-15, and 19 are anticipated by Weiss.
With regard to claim 20, Weiss discloses a composition comprising a compound of formula Ia or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier. [page 180, [0290].
With regard to claims 22-23, Weiss discloses a method of using the compounds of formula Ia i.e., I-3, in degrading and/or inhibiting one of more of IRAK-1, IRAK-2, and/or IRAK-4, and a method for treating a IRAK-1-mediated, a IRAK-2-mediated, and/or a IRAK-4-mediated disorder comprising the step of administering to a patient in need thereof a compound of formula Ia i.e., I-3, or pharmaceutically acceptable composition thereof. [page 183, [0318]].
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 (i.e., changing from AIA to pre-AIA ) 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 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 1-8, 10-15, 17-20, and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over M. Weiss (US PG PUB 2023/0144292A1, 05/11/2023, “Weiss” cited in the IDS dated 01/05/2024) in view of N. Meanwell, J. Med. Chem. 2011, VL 54, IS 8, SN 0022-2623, PP 2529 EP- 2591, “Meanwell” cited in the PTO-892) .
Prior Art Effect of Weiss
The earliest possible effective filing date of the subject claims is that of priority document U.S. Provisional Application No. 63/185,921, filed on 05/07/2021. Weiss is effective prior art under 35 USC § 102(a)(2) respecting the subject matter cited in this rejection as of the filing date of Weiss priority document U.S. Provisional Application No. 62/949,298 filed on 12/17/2019 because: (1) Weiss is U.S. patent application publication; (2) names another inventor; and (3) the subject matter of Weiss relied upon in this rejection is disclosed in Weiss’s priority document U.S. Provisional Application No. 62/949,298 (12/17/2019). See MPEP § 2154.01; 35 USC § 102(d). Thus, the effective filing date of the subject matter relied upon in this rejection is 12/17/2019, which is before the claims’ earlies possible effective filing date of 05/07/2021. See MPEP § 2154.01; 35 USC § 102(d).
Joint Inventorship
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 disclosures set forth above in the 102 Rejection over the same Weiss reference are herein incorporated by reference.
Weiss is applied to claims 1-8, 13-15, 19-20, and 22-23 as discussed above, and incorporated herein.
While deuterium is hydrogen isotope naturally involved with all the hydrogens of Weiss compound I-3. However, Weiss does not specifically teach that the deuterium is incorporated at about 80-95%.
However, Weiss discloses that structures depicted herein are also meant to include compounds that differ only in the presence of one or more deuterium, e.g., compounds having the present structures including the replacement of hydrogen by deuterium [page 5, [0048]]. Weiss discloses that the formula Ia defines Rx and Ry as H or deuterium. [page 6, 7, [0061], [0065]], Weiss teaches that in some embodiment, each Rx is deuterium. [page 7, [0076]], in some embodiment, each Ry is deuterium. [page 8, [0084]].
Meanwell teaches replacement of H with deuterium in drug design. Meanwell teaches that substituting a H atom by D represents the most conservative example of bioisosterism because of the similarities between the two isotopes. Meanwell teaches that substituting a H atom by D offers significant advantages including modulates drug metabolism, improves pharmacokinetic properties, modulate toxicity, [page 2530, col. 2], increase drug stability and slow epimerization, [page 2531, col. 1, 1st para.], reduces lipophilicity, increases the basicity of amines while the acidity of phenols and carboxylic acids is decreased. [page 2530, col. 1, 1st para.].
In view of the foregoing teachings of Weiss and Meanwell, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to increase the incorporation of deuterium in Weiss’s compound I-3 to more than 80% and replace the hydrogen of I-3 with deuterium. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because:
Weiss discloses that the compounds i.e., I-3 have the hydrogen replace with deuterium [0048];
Weiss discloses that each Rx and Ry is deuterium. [0076]], [0084];
Weiss discloses that compound I-3 degrade IRAK4 at 24 hours with an DC50 of less than 0.05 µM, and at 4 hours with an DC50 of 0.05-0.1 µM. [page 224, Table 5]. Note that I-3 not only one of the potent IRAK4 of Weiss, but it’s the only compound that degrade IRAKA at 4 hours.
Meanwell teaches that substituting hydrogen atoms by deuterium modulates drug metabolism, improves pharmacokinetic properties, modulate toxicity, [page 2530, col. 2];
Meanwell teaches that substituting hydrogen atoms by deuterium increase drug stability and slow epimerization, [page 2531, col. 1, 1st para.], reduces lipophilicity;
Meanwell teaches that substituting hydrogen atoms by deuterium is advantageous because deuterium is slightly less lipophilic than hydrogen; the molar volume of deuterium is smaller than hydrogen; C-D bonds are shorter than C-H bonds.
As such, an ordinary skilled artisan would have been motivated to substitute the hydrogen with deuterium and increase the deuterium in the compound by more than 80%, to predictably arrive at the compounds of claims 10-12, and 17-18.
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.
Non-Statutory Double Patenting over U.S. Patent No. 11,707,457 B2
Claims 1-8, 13-15, 19-20, and 22-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,707,457 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 1 recites:
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whereas claims 2-8, 13-15, and 19 recite that one or more of the above R1-48 is D, and claim 20 recites a composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
U.S. Patent No. 11707457B2 recites in claim 1 compound I-3:
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U.S. Patent No. 11707457B2 compound I-3 anticipates claim 1 formula I wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R", R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, and R48 are H.
With regard to the claim 1 limitation “at least one of the above listed R1-48 is D”:
As well known in the art, hydrogen consists of three isotopes: (1) hydrogen or protium (P or H), (2) deuterium (D); and (3) tritium (T), with mass numbers 1, 2 and 3 respectively. The natural isotopic abundance of Hydrogen 1H is 99.985 % and that of 2H is 0.015 %. W. Meier-Augenstein et al., Stable Isotope Analysis: General Principles and Limitations, In Wiley Encyclopedia of Forensic Science, 1-15 (2012). Also, it more common to find deuterium bonded to a protium atom to form hydrogen deuteride, which is written as HD or 1H2H.See A. M. Helmenstine, Deuterium Facts, 2019. Thus, deuterium is involved in every synthetic reaction in which hydrogen is employed.
Therefore, claims 1-8, 13-15, and 19 are anticipated by U.S. Patent No. 11707457B2.
With regard to claim 20, U.S. Patent No. 11707457B2 recites in claim 26 a pharmaceutical composition comprising the compound I-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
With regard to claim 22-23, U.S. Patent No. 11707457B2 specification recited a method of using the compound I-3, in degrading and/or inhibiting one of more of IRAK-1, IRAK-2, and/or IRAK-4, and a method for treating a IRAK-1-mediated, a IRAK-2-mediated, and/or a IRAK-4-mediated disorder comprising the step of administering to a patient in need thereof a compound of formula Ia i.e., I-3, or pharmaceutically acceptable composition thereof. [Col. 345, ln. 58-67]. MPEP 804 states: The specification can be used as a dictionary to learn the meaning of a term in the claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999) ("[W]ords in patent claims are given their ordinary meaning in the usage of the field of the invention, unless the text of the patent makes clear that a word was used with a special meaning."); Renishaw PLC v. Marposs Societa' per Azioni, 158 F.3d 1243, 1250, 48 USPQ2d 1117, 1122 (Fed. Cir. 1998) ("Where there are several common meanings for a claim term, the patent disclosure serves to point away from the improper meanings and toward the proper meanings."). "The Patent and Trademark Office (‘PTO’) determines the scope of the claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction ‘in light of the specification as it would be interpreted by one of ordinary skill in the art.’ " Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005) (en banc) (quoting In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364, 70 USPQ2d 1827, 1830 (Fed. Cir. 2004); see also MPEP § 2111.01. Further, those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970). The court in Vogel recognized "that it is most difficult, if not meaningless, to try to say what is or is not an obvious variation of a claim," but that one can judge whether or not the invention claimed in an application is an obvious variation of an embodiment disclosed in the patent or application which provides support for the claim. According to the court, one must first "determine how much of the patent disclosure pertains to the invention claimed in the patent" because only "[t]his portion of the specification supports the patent claims and may be considered." The court pointed out that "this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined." In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010); Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003).
Non-Statutory Double Patenting over U.S. Patent No. 11707457B2 in view of Meanwell
Claims 10-12, and 17-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11707457B2, as applied above to claims 1-8, 13-15, 19-20, and 22-23 in view of N. Meanwell, J. Med. Chem. 2011, VL 54, IS 8, SN 0022-2623, PP 2529 EP- 2591, “Meanwell” cited in the PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because:
While deuterium is hydrogen isotope naturally involved with all the hydrogens of U.S. Patent No. 11707457B2 compound I-3. However, U.S. Patent No. 11707457B2 does not specifically teach that the deuterium incorporated by about 80-95%.
Meanwell teaches replacement of H with deuterium in drug design. Meanwell teaches that substituting a H atom by D represents the most conservative example of bioisosterism because of the similarities between the two isotopes. Meanwell teaches that substituting a H atom by D offers significant advantages including modulates drug metabolism, improves pharmacokinetic properties, modulate toxicity, [page 2530, col. 2], increase drug stability and slow epimerization, [page 2531, col. 1, 1st para.], reduces lipophilicity, increases the basicity of amines while the acidity of phenols and carboxylic acids is decreased. [page 2530, col. 1, 1st para.].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to increase the incorporation of deuterium in U.S. Patent No. 11707457B2 compound I-3 to more than 80% and replace the hydrogen of I-3 with deuterium. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because:
Meanwell teaches that substituting hydrogen atoms by deuterium modulates drug metabolism, improves pharmacokinetic properties, modulate toxicity, [page 2530, col. 2];
Meanwell teaches that substituting hydrogen atoms by deuterium increase drug stability and slow epimerization, [page 2531, col. 1, 1st para.], reduces lipophilicity;
Meanwell teaches that substituting hydrogen atoms by deuterium is advantageous because deuterium is slightly less lipophilic than hydrogen; the molar volume of deuterium is smaller than hydrogen; C-D bonds are shorter than C-H bonds.
As such, an ordinary skilled artisan would have been motivated to substitute the hydrogen with deuterium and increase the deuterium in the compound by more than 80%, to predictably arrive at the compounds of claims 10-12, and 17-18.
Non-Statutory Double Patenting over U.S. Patent No. 11779578B2
Claims 1-8, 13-15, 19-20, and 22-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11779578B2. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 1 recites:
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whereas claims 2-8, 13-15, and 19 recite that one or more of the above R1-48 is D, and claim 20 recites a composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
U.S. Patent No. 11779578B2 recites in claim 1 a compound of formula I-a-5, wherein Rx and Ry defined as H, D, etc., and recites in claim 4 compound I-3 as species of formula I-a-5:
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With regard to the claim 1 limitation “at least one of the above listed R1-48 is D”:
As well known in the art, hydrogen consists of three isotopes: (1) hydrogen or protium (P or H), (2) deuterium (D); and (3) tritium (T), with mass numbers 1, 2 and 3 respectively. The natural isotopic abundance of Hydrogen 1H is 99.985 % and that of 2H is 0.015 %. W. Meier-Augenstein et al., Stable Isotope Analysis: General Principles and Limitations, In Wiley Encyclopedia of Forensic Science, 1-15 (2012). Also, it more common to find deuterium bonded to a protium atom to form hydrogen deuteride, which is written as HD or 1H2H.See A. M. Helmenstine, Deuterium Facts, 2019. Thus, deuterium is involved in every synthetic reaction in which hydrogen is employed.
Therefore, claims 1-8, 13-15, and 19 are anticipated by U.S. Patent No. 11779578B2.
With regard to claim 20, U.S. Patent No. 11779578B2 recites in claim 19 a pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
With regard to claim 22-23, U.S. Patent No. 11779578B2 specification recited a method of using the compound I-3, in degrading and/or inhibiting one of more of IRAK-1, IRAK-2, and/or IRAK-4, and a method for treating a IRAK-1-mediated, a IRAK-2-mediated, and/or a IRAK-4-mediated disorder comprising the step of administering to a patient in need thereof a compound of formula Ia i.e., I-3, or pharmaceutically acceptable composition thereof. [Col. 369, ln. 11-16]. Claims 22-23 are met in view of the MPEP 804 explanation on pages 11-12 above.
Non-Statutory Double Patenting over U.S. Patent No. 11779578B2 in view of Meanwell
Claims 10-12, and 17-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11779578B2, as applied above to claims 1-8, 13-15, 19-20, and 22-23 in view of N. Meanwell, J. Med. Chem. 2011, VL 54, IS 8, SN 0022-2623, PP 2529 EP- 2591, “Meanwell” cited in the PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because:
While deuterium is hydrogen isotope naturally involved with all the hydrogens of U.S. Patent No. 11779578B2 compound I-3. However, U.S. Patent No. 11779578B2 does not specifically teach that the deuterium incorporated by about 80-95%.
Meanwell teaches replacement of H with deuterium in drug design. Meanwell teaches that substituting a H atom by D represents the most conservative example of bioisosterism because of the similarities between the two isotopes. Meanwell teaches that substituting a H atom by D offers significant advantages including modulates drug metabolism, improves pharmacokinetic properties, modulate toxicity, [page 2530, col. 2], increase drug stability and slow epimerization, [page 2531, col. 1, 1st para.], reduces lipophilicity, increases the basicity of amines while the acidity of phenols and carboxylic acids is decreased. [page 2530, col. 1, 1st para.].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to increase the incorporation of deuterium in U.S. Patent No. 11779578B2 compound I-3 to more than 80% and replace the hydrogen of I-3 with deuterium. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because:
Meanwell teaches that substituting hydrogen atoms by deuterium modulates drug metabolism, improves pharmacokinetic properties, modulate toxicity, [page 2530, col. 2];
Meanwell teaches that substituting hydrogen atoms by deuterium increase drug stability and slow epimerization, [page 2531, col. 1, 1st para.], reduces lipophilicity;
Meanwell teaches that substituting hydrogen atoms by deuterium is advantageous because deuterium is slightly less lipophilic than hydrogen; the molar volume of deuterium is smaller than hydrogen; C-D bonds are shorter than C-H bonds.
As such, an ordinary skilled artisan would have been motivated to substitute the hydrogen with deuterium and increase the deuterium in the compound by more than 80%, to predictably arrive at the compounds of claims 10-12, and 17-18.
Non-Statutory Double Patenting over U.S. Patent No. 11857535B2
Claims 1-8, 13-15, 19-20, and 22-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 25 of U.S. Patent No. 11857535B2. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 1 recites:
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whereas claims 2-8, 13-15, and 19 recite that one or more of the above R1-48 is D, and claim 20 recites a composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
U.S. Patent No. 11857535B2 recites in claim 1 a method of treating a MYD88-mutant B-cell lymphoma in a patient in need thereof, comprising administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof to the patient, wherein compound A degrade IRAK4 and MYD88-mutant B-cell lymphoma is an IRAK4 mediated disease:
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With regard to the claim 1 limitation “at least one of the above listed R1-48 is D”:
As well known in the art, hydrogen consists of three isotopes: (1) hydrogen or protium (P or H), (2) deuterium (D); and (3) tritium (T), with mass numbers 1, 2 and 3 respectively. The natural isotopic abundance of Hydrogen 1H is 99.985 % and that of 2H is 0.015 %. W. Meier-Augenstein et al., Stable Isotope Analysis: General Principles and Limitations, In Wiley Encyclopedia of Forensic Science, 1-15 (2012). Also, it more common to find deuterium bonded to a protium atom to form hydrogen deuteride, which is written as HD or 1H2H.See A. M. Helmenstine, Deuterium Facts, 2019. Thus, deuterium is involved in every synthetic reaction in which hydrogen is employed.
Therefore, claims 1-8, 13-15, 19, 22-23 and are anticipated by U.S. Patent No. 11857535B2.
With regard to claim 20, U.S. Patent No. 11857535B2 recites in claim 25 Compound A or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition comprising one or more pharmaceutically acceptable excipient or carrier.
Non-Statutory Double Patenting over U.S. Patent No. 11857535B2 in view of Meanwell
Claims 10-12, and 17-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11857535B2, as applied above to claims 1-8, 13-15, 19-20, and 22-23 in view of N. Meanwell, J. Med. Chem. 2011, VL 54, IS 8, SN 0022-2623, PP 2529 EP- 2591, “Meanwell” cited in the PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because:
While deuterium is hydrogen isotope naturally involved with all the hydrogens of U.S. Patent No. 11857535B2 Compound A. However, U.S. Patent No. 11857535B2 does not specifically teach that the deuterium incorporated by about 80-95%.
Meanwell teaches replacement of H with deuterium in drug design. Meanwell teaches that substituting a H atom by D represents the most conservative example of bioisosterism because of the similarities between the two isotopes. Meanwell teaches that substituting a H atom by D offers significant advantages including modulates drug metabolism, improves pharmacokinetic properties, modulate toxicity, [page 2530, col. 2], increase drug stability and slow epimerization, [page 2531, col. 1, 1st para.], reduces lipophilicity, increases the basicity of amines while the acidity of phenols and carboxylic acids is decreased. [page 2530, col. 1, 1st para.].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to increase the incorporation of deuterium in U.S. Patent No. 11857535B2 Compound A to more than 80% and replace the hydrogen with deuterium. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because:
Meanwell teaches that substituting hydrogen atoms by deuterium modulates drug metabolism, improves pharmacokinetic properties, modulate toxicity, [page 2530, col. 2];
Meanwell teaches that substituting hydrogen atoms by deuterium increase drug stability and slow epimerization, [page 2531, col. 1, 1st para.], reduces lipophilicity;
Meanwell teaches that substituting hydrogen atoms by deuterium is advantageous because deuterium is slightly less lipophilic than hydrogen; the molar volume of deuterium is smaller than hydrogen; C-D bonds are shorter than C-H bonds.
As such, an ordinary skilled artisan would have been motivated to substitute the hydrogen with deuterium and increase the deuterium in the compound by more than 80%, to predictably arrive at the compounds of claims 10-12, and 17-18.
Non-Statutory Double Patenting over Copending Application No. 18/360,277
Claims 1-8, 13-15, 19-20, and 22-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10 and 13-29 of Copending Application No. 18/360,277 (US20240131016A1). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claim 1 recites:
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whereas claims 2-8, 13-15, and 19 recite that one or more of the above R1-48 is D, and claim 20 recites a composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
Copending Application No. 18/360,277 recites in claim 1 a method of treating an IRAK4 mediated disorder, disease, or condition comprising administering to a patient a compound of formula I-a-5, and recites in claim 29 compound I-3 as species of formula I-a-5:
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With regard to the claim 1 limitation “at least one of the above listed R1-48 is D”:
As well known in the art, hydrogen consists of three isotopes: (1) hydrogen or protium (P or H), (2) deuterium (D); and (3) tritium (T), with mass numbers 1, 2 and 3 respectively. The natural isotopic abundance of Hydrogen 1H is 99.985 % and that of 2H is 0.015 %. W. Meier-Augenstein et al., Stable Isotope Analysis: General Principles and Limitations, In Wiley Encyclopedia of Forensic Science, 1-15 (2012). Also, it more common to find deuterium bonded to a protium atom to form hydrogen deuteride, which is written as HD or 1H2H.See A. M. Helmenstine, Deuterium Facts, 2019. Thus, deuterium is involved in every synthetic reaction in which hydrogen is employed.
Therefore, claims 1-8, 13-15, 19, 20, and 22-23 are anticipated by Copending Application No. 18/360,277.
Non-Statutory Double Patenting over Copending Application No. 18/360,277 in view of Meanwell
Claims 10-12, and 17-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10 and 13-29 of Copending Application No. 18/360,277 (US PG PUB 2024/0131016A1), as applied above to claims 1-8, 13-15, 19-20, and 22-23 in view of N. Meanwell, J. Med. Chem. 2011, VL 54, IS 8, SN 0022-2623, PP 2529 EP- 2591, “Meanwell” cited in the PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because:
While deuterium is hydrogen isotope naturally involved with all the hydrogens of Copending Application No. 18/360,277 compound I-3. However, Copending Application No. 18/360,277 does not specifically teach that the deuterium incorporated by about 80-95%.
Meanwell teaches replacement of H with deuterium in drug design. Meanwell teaches that substituting a H atom by D represents the most conservative example of bioisosterism because of the similarities between the two isotopes. Meanwell teaches that substituting a H atom by D offers significant advantages including modulates drug metabolism, improves pharmacokinetic properties, modulate toxicity, [page 2530, col. 2], increase drug stability and slow epimerization, [page 2531, col. 1, 1st para.], reduces lipophilicity, increases the basicity of amines while the acidity of phenols and carboxylic acids is decreased. [page 2530, col. 1, 1st para.].
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of instantly claimed invention to increase the incorporation of deuterium in Copending Application No. 18/360,277 compound I-3 to more than 80% and replace the hydrogen with deuterium. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because:
Meanwell teaches that substituting hydrogen atoms by deuterium modulates drug metabolism, improves pharmacokinetic properties, modulate toxicity, [page 2530, col. 2];
Meanwell teaches that substituting hydrogen atoms by deuterium increase drug stability and slow epimerization, [page 2531, col. 1, 1st para.], reduces lipophilicity;
Meanwell teaches that substituting hydrogen atoms by deuterium is advantageous because deuterium is slightly less lipophilic than hydrogen; the molar volume of deuterium is smaller than hydrogen; C-D bonds are shorter than C-H bonds.
As such, an ordinary skilled artisan would have been motivated to substitute the hydrogen with deuterium and increase the deuterium in the compound by more than 80%, to predictably arrive at the compounds of claims 10-12, and 17-18.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-8, 10-15, 17-20, and 22-23 are rejected. No claim is allowed.
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/M.M.A./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622