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 election of Group I, claims 2-4, 7-9, 12, 15, 17, 26, 29, 33, 37, 44, 46, 50, 52, 64, 65, 68-73, and 76, as well as the species: compound 2g of claim 76, wherein
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Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
It is noted that the elected species (2g) comprises a linker of Dibenzocyclooctyl-NH-Peg4-Val-Cit-PAB, a spacer of -C(O)-CH2-CH2-C(O)-, and a budesonide.
Claims 2-4, 7-9, 12, 15, 17, 26, 29, 33, 37, 44, 46, 50, 52, 64, 65, 68-73, 76-83, 85, 88, 91-95, 99, and 101 are pending.
Claims 4, 12, 15, 17, 26, 29, 33, 37, 44, 46, 50, 72, 77-83, 85, 88, 91-95, 99, and 101 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions or species, there being no allowable generic or linking claim.
Claims 2, 3, 7-9, 52, 64, 65, 68-71, 73, and 76 are examined to the extent of elected species.
Priority
It is acknowledged that this application is a divisional of US Application No. 16/243,020 filed January 8, 2019, which claims the benefit of priority to U.S. Provisional Patent Appl. No. 62/614, 905 filed January 8, 2018. The priority date has been established as: January 8, 2018.
Information Disclosure Statement
The Information Disclosure Statements filed on 08/23/2024, 11/01/2024, 01/05/2026 and 08/11/2026 have been considered and entered by examiner.
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.
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.
Claims 2, 3, 8-9, 52, 64, 65, 68-71, 73, and 76 are rejected under 35 U.S.C. 103 as being unpatentable over Bregeon (Bregeon et al., Pub. No.: US 2015/0165064 A1, Publication Date: 06-18-2015, cited in IDS of 08/23/2024), in view of Kern (Kern et al., Bioconjugate Chem. 2016, 27, 2081-2088, Publication Date: 07-28-2016, cited in IDS of 08/23/2024), Teitelbaum (Teitelbaum et al., Bioorg. Med. Chem., 21 (2013) 5605-5617, Publication Date: 05/24/2013), and Varshosaz (Varshosaz et al., International Journal of Pharmaceutics, 365, (2009) 69-76, Publication Date: 08/30/2008, cited in IDS of 08/23/2024).
It is noted that the elected species (2g) comprises a linker of Dibenzocyclooctyl-NH-Peg4-Val-Cit-PAB, a spacer of -C(O)-CH2-CH2-C(O)-, and a budesonide. Compound 2g would read on claims 2, 3, 8-9, 52, 64, 65, 68-71, 73, and 76, as recognized by applicant (see Applicant’s remarks filed on August 11, 2026).
Bregeon teaches that immunoglobulins conjugated to a drug of interest, generally known as antibody drug conjugates (ADCs), are a promising area of therapeutic research ([0004]).
Bregeon teaches that an antibody reacts with a linking comprising a complementary reactive group and a drug to yield an antibody coupled to the drug ([0012]). Bregeon teaches methods of making ADCs (claim 1).
Bregeon teaches various ADC formula (claim 16, Tables 8-10).
Bregeon teaches a compound which has a DBCO-NH-PEG4-Val-Cit-PAB linker and an attached payload (MMAE) (Example 11). This compound can be used to make antibody-drug conjugates (Example 13).
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Bregeon teaches that each antibody can have 4 payloads (antibody composition have (m) functionalized acceptor glutamine residues (Q) per antibody, wherein m is an integer selected from 1, 2, 3, or 4 ([0255]); two acceptor glutamines per antibody heavy chain, provides a strategy to couple moieties of interest onto four acceptor glutamines per full antibody ([0857]).
Bregeon teaches that the linker has improved processes for click-chemistry functionalization, improved stability, and high efficacy (Examples 11-13, Tables 9-10).
Bregeon teaches that a wide range of antibodies and drugs can be used for making ADCs ([0054], [0371]-[0375], [0599]).
Bregeon teaches as set forth above. However, Bregeon does not teach an ADC wherein the drug is budesonide, or an additional spacer of -C(O)-CH2-CH2-C(O)- between PAB and budesonide.
Kern teaches that antibody drug conjugates (ADCs) have been developed to deliver drug to targeted location (§ Introduction).
Kern teaches that targeted delivery of glucocorticoid steroids to immune cells for the potential treatment of immunological diseases (page 2081, col. 2, para. 2).
Kern teaches that ADC with budesonide would have impressive potency and short circulating half-life, which would aid in limiting systemic concentrations and further decrease the risk of undesired effects (page 2081, col. 2, para. 2).
Kern teaches that the connection between PABC and budesonide is a carbonate bond (-O-C(O)-O-) (see compound 2 of Figure 1). The carbonate bond shows blood instability (§ CONCLUSIONS).
Consistent with Kern, Teitelbaum teaches that drug-linker connected with a carbonate bond (-O-C(O)-O-) have very short half-lives, indicating poor plasma stability (Table 3), which might affect the oral absorption of the drugs (§ Conclusions).
Varshosaz teaches that budesonide is a potent glucocorticoid with high local anti-inflammatory effect and low systemic bioavailability due to the result of extensive first pass metabolism. Budesonide is available in two controlled release oral dosage forms, Budenofalk® and Entocort®. These two formulations deliver the drug to the ileum and ascending colon and only a small fraction of the active molecule is released in transverse and descending colon and consequently they are less effective in the treatment of ulcerative colitis. Thus, designing and developing a system which could deliver budesonide to the colon seems imperative (page 70, col. 1, para. 2).
Varshosaz teaches a budesonide conjugate using succinate as the spacer (Fig. 1) which would generate a spacer of -C(O)-CH2-CH2-C(O)- (see bottom structure of Fig. 1).
Varshosaz teaches that since budesonide does not have any carboxylic acid group, succinic anhydride was used to insert a carboxylic group at C21 of budesonide (page 74, the bottom paragraph of col. 2). Varshosaz also teaches the method of making budesonide-21-hemisuccinate (compound 3 of Figure 1).
Varshosaz teaches that the conjugates made from budesonide-21-hemisuccinate are stable at pH of stomach and small intestine (page 73, the bottom paragraph of col. 2).
Varshosaz teaches that the ester bond between the drug and the spacer and between the spacer and linker (polymer) could be hydrolyzed by the esterases of the GI tract (page 76, col. 1, para. 1).
Varshosaz teaches that cumulative release profiles of the conjugates indicated that these budesonide conjugate has a significant increase in the presence of the contents of caecum and colon (page 76, col. 1, para. 1; and Fig. 3). In addition, budesonide hemisuccinate also has good affinity toward the receptor and could trigger anti-inflammatory effects (page 76, col. 1, para. 2).
It would have prima facie been obvious to one of ordinarily skilled in the art before the time the invention was filed to make a DBCO-NH-PEG4-Val-Cit-PAB-drug (e.g. DBCO-NH-PEG4-Val-Cit-PAB-MMAE) as taught by Bregeon, and to replace the MMAE with budesonide and to add a spacer of -C(O)-CH2-CH2-C(O)- between PAB and budesonide through ester bonds because the carbonate bond (-O-C(O)-O-) have very short half-lives and poor plasma stability and adding a spacer of -C(O)-CH2-CH2-C(O)- would improve the stability of the conjugate, as taught by Kern, Teitelbaum and Varshosaz. One of ordinary skill in the art would have a reasonable expectation because 1) Bregeon teaches DBCO-NH-PEG4-Val-Cit-PAB-drug can be used for making ADCs for different antibodies and different drugs with precise linkage to multiple antibodies; 2) Kern and Varshosaz teach that budesonide-antibody conjugate can further improve therapeutic properties of budesonide; 3) direct link PAB and budesonide would form a carbonate bond (taught by Kern) and drug conjugates with a carbonate bond linker have poor plasma stability (taught by Teitelbaum); 4) Varshosaz teaches inserting a carboxylic group at C21 of budesonide by succinic anhydride and the ester bond between the drug and the spacer and between the spacer and linker could be hydrolyzed by the esterases of the GI tract. Based on the teachings of the references, one of ordinary skill in the art would have a reasonable expectation to reach the elected species: DBCO-NH-PEG4-Val-Cit-PAB-spacer-budesonide, wherein the spacer is -C(O)-CH2-CH2-C(O)-, because this compound would have an improved stability and be useful to make a good antibody-budesonide conjugate with good stability and good activity for treating inflammatory condition in colon. The motivation would have been to expand the options for budesonide-antibody conjugates.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Bregeon (Bregeon et al., Pub. No.: US 2015/0165064 A1, Publication Date: 06-18-2015, cited in IDS of 08/23/2024), Kern (Kern et al., Bioconjugate Chem. 2016, 27, 2081-2088, Publication Date: 07-28-2016, cited in IDS of 08/23/2024), Teitelbaum (Teitelbaum et al., Bioorg. Med. Chem., 21 (2013) 5605-5617, Publication Date: 05/24/2013), and Varshosaz (Varshosaz et al., International Journal of Pharmaceutics, 365, (2009) 69-76, Publication Date: 08/30/2008, cited in IDS of 08/23/2024), as applied to claims 2, 3, 8-9, 52, 64, 65, 68-71, 73, and 76 above, and further in view of Lemke (Lemke et al., Foye’s Principles of Medicinal Chemistry, Chapter 44, pp. 1253, Publication Year: 2008, cited in IDS of 08/23/2024).
Bregeon, Kern, Teitelbaum and Varshosaz teach the Compound of Formula (II) as set forth above, however, Bregeon, Kern, Teitelbaum and Varshosaz do not teach that R4 group is in the (R)-configuration.
Lemke teaches that the R-epimer was two-fold more active than the S-epimer, in receptor affinity study.
It would have prima facie been obvious to one of ordinarily skilled in the art before the time the invention was filed to relate the teaching of Bregeon, Kern, Teitelbaum, Varshosaz and Lemke to use R-budesonide, which is more active than S-budesonide, in the ADC, because doing so would potentially enhance the therapeutic efficacy of the antibody-budesonide conjugate, as taught by Lemke.
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 2, 3, 7-9, 52, 64, 65, 68-71, 73, and 76 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,760,775 B2 (hereinafter referred to as “reference patent”, cited in IDS of 09/10/2024), in view of Bregeon (Bregeon et al., Pub. No.: US 2015/0165064 A1, Publication Date: 06-18-2015, cited in IDS of 08/23/2024), Kern (Kern et al., Bioconjugate Chem. 2016, 27, 2081-2088, Publication Date: 07-28-2016, cited in IDS of 08/23/2024), Teitelbaum (Teitelbaum et al., Bioorg. Med. Chem., 21 (2013) 5605-5617, Publication Date: 05/24/2013), and Varshosaz (Varshosaz et al., International Journal of Pharmaceutics, 365, (2009) 69-76, Publication Date: 08/30/2008, cited in IDS of 08/23/2024) for the instant claims 2, 3, 8-9, 52, 64, 65, 68-71, 73, and 76, and further in view of Lemke (Lemke et al., Foye’s Principles of Medicinal Chemistry, Chapter 44, pp. 1253, Publication Year: 2008, cited in IDS of 08/23/2024) for the instant claim 7.
Claims 2, 3, 7-9, 52, 64, 65, 68-71, 73, and 76 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 rejection, the 103 being incorporated here. The addition of the patented claims of the reference patent over related subject matter only further supports this obviousness.
Reference patent claim 1 is drawn to a conjugate compound comprising an antibody or antigen binding fragment conjugated to a compound of Formula A, shown below.
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It is specifically noted that in Formula A: R1 and R2 are independently hydrogen, alkyl, alkyl-C(O)-O-, -OH, halo or may together form the structure shown below wherein R4 may be alkyl, aryl, arylalkyl, or a nitrogen-containing heterocycloalkyl; R3 is -NRaRb wherein Ra and Rb may each independently be hydrogen, alkyl, an optionally substituted aryl, or may cyclize to form a cycloheteroalkyl comprising the nitrogen atom they are attached to; R5 is independently -OH, halo, alkyl, or arylalkyl positioned on any ring atom where n is an integer from 0-19; and the antibody or antigen binding fragment thereof is covalently bonded to R3.
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Reference patent claims 2-5 further specify structures of conjugate compounds and show below are exemplary conjugate compounds of reference patent claim 4. Reference patent claim 5 discloses full conjugate structures wherein the linker and BA structures are provided, e.g. the structure shown below comprising a glucocorticoid, a spacer, a DBCO-PEG4-Val-Cit-PABC linker and a
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:
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Claim 5 of reference patent is considered to be most closely related to the instant invention. Thus, the reference patent is generally drawn to steroid compounds and conjugates thereof. However, it is noted that the reference patent does not specifically disclose the elected compound of the instant invention, which can be considered as the intermediate product for making ADCs of the reference patent, particularly with regard to the budesonide, SP structure of the elected species, and/or R4 in the R-configuration. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
The above-listed reference patents, Bregeon, Kern, Teitelbaum, Varshosaz and Lemke are considered to be analogous to the present invention as they are in the same field of biologically active compounds/agents and their modification for improved delivery/efficacy. Thus, it would have been obvious to one of ordinary skill in the art that the compounds of the reference patent claims could be modified to make the precursor of an ADC: DBCO-NH-PEG4-Val-Cit-PAB-drug (e.g. DBCO-NH-PEG4-Val-Cit-PAB-MMAE) as taught by Bregeon, and to replace the MMAE with budesonide and to add a spacer of -C(O)-CH2-CH2-C(O)- between PAB and budesonide through ester bonds, because the carbonate bond (-O-C(O)-O-) have very short half-lives and poor plasma stability and adding a spacer of -C(O)-CH2-CH2-C(O)- would improve the stability of the conjugate, as taught by Kern, Teitelbaum and Varshosaz. One of ordinary skill in the art would have a reasonable expectation because 1) Bregeon teaches DBCO-NH-PEG4-Val-Cit-PAB-drug can be used for making ADCs for different antibodies and different drugs with precise linkage to multiple antibodies; 2) Kern and Varshosaz teach that budesonide-antibody conjugate can further improve therapeutic properties of budesonide; 3) direct link PAB and budesonide would form a carbonate bond (taught by Kern) and drug conjugates with a carbonate bond linker have poor plasma stability (taught by Teitelbaum); 4) Varshosaz teaches inserting a carboxylic group at C21 of budesonide by succinic anhydride and the ester bond between the drug and the spacer and between the spacer and linker could be hydrolyzed by the esterases of the GI tract. Based on the teachings of the references, one of ordinary skill in the art would have a reasonable expectation to reach the elected species: DBCO-NH-PEG4-Val-Cit-PAB-spacer-budesonide, wherein the spacer is -C(O)-CH2-CH2-C(O)-, because the carbonate bond (-O-C(O)-O-) have very short half-lives and poor plasma stability and adding a spacer of -C(O)-CH2-CH2-C(O)- would improve the stability of the conjugate. This compound would be useful to make a good antibody-budesonide conjugate with good stability and good activity for treating inflammatory condition in colon. The motivation would have been to expand the options for budesonide-antibody conjugates.
One of ordinary skill in the art would be motivated to modify the compounds of the reference patents based on the teachings of Bregeon, Kern, Teitelbaum, Varshosaz, and Lemke, to arrive at the instantly claimed compound (e.g. the elected compound of instant claim 76), wherein such a compound could be conjugated to an antibody as suggested by Bregeon, in order to facilitate targeted delivery of the steroid payload to target cells, targeted by the antibody, which would be useful in the treatment of, for example, immunological diseases in colon as taught by Kern, Teitelbaum, and Varshosaz.
Similarly, claims 2, 3, 7-9, 52, 64, 65, 68-71, 73, and 76 are rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the U.S. Patent Nos. listed below in view of in view of Bregeon (Bregeon et al., Pub. No.: US 2015/0165064 A1, Publication Date: 06-18-2015, cited in IDS of 08/23/2024), Kern (Kern et al., Bioconjugate Chem. 2016, 27, 2081-2088, Publication Date: 07-28-2016, cited in IDS of 08/23/2024), Teitelbaum (Teitelbaum et al., Bioorg. Med. Chem., 21 (2013) 5605-5617, Publication Date: 05/24/2013), and Varshosaz (Varshosaz et al., International Journal of Pharmaceutics, 365, (2009) 69-76, Publication Date: 08/30/2008, cited in IDS of 08/23/2024) for the instant claims 2, 3, 8-9, 52, 64, 65, 68-71, 73, and 76, and further in view of Lemke (Lemke et al., Foye’s Principles of Medicinal Chemistry, Chapter 44, pp. 1253, Publication Year: 2008, cited in IDS of 08/23/2024) for the instant claim 7.
Patent No.
Brief Description of the Invention
Pertinent Claims
10711032
Steroid Compounds and Conjugates Thereof
1-10, 15
12070506
Steroid Compounds and Conjugates Thereof
1-21
12377159
Steroid Compounds and Conjugates Thereof
1-23
12497460
Steroid Compounds and Conjugates Thereof
1-33
It is noted that Pat. No. 10711032 was cited in IDS of 08/23/2024; 12070506 was cited in IDS of 11/01/2024; and 12377159 was cited in IDS of 01/05/2026.
Claims 2, 3, 7-9, 52, 64, 65, 68-71, 73, and 76 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 rejection, the 103 being incorporated here. The addition of the patented claims of the reference patent over related subject matter only further supports this obviousness.
It is specifically noted that all of the above-listed reference patents are drawn to steroid compounds and conjugates thereof, wherein the steroid compounds all have similar/overlapping structures with those of the reference patent 11,760,775 as presented above. However, it is noted that the reference patent does not specifically disclose the elected compound of the instant invention, which can be considered as the intermediate product for making ADCs of the reference patent, particularly with regard to the budesonide, SP structure of the elected species, and/or R4 in the R-configuration. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
The above-listed reference patents, Bregeon, Kern, Teitelbaum, Varshosaz and Lemke are considered to be analogous to the present invention as they are in the same field of biologically active compounds/agents and their modification for improved delivery/efficacy. Thus, it would have been obvious to one of ordinary skill in the art that the compounds of the reference patent claims could be modified to make the precursor of an ADC: DBCO-NH-PEG4-Val-Cit-PAB-drug (e.g. DBCO-NH-PEG4-Val-Cit-PAB-MMAE) as taught by Bregeon, and to replace the MMAE with budesonide and to add a spacer of -C(O)-CH2-CH2-C(O)- between PAB and budesonide through ester bonds, because the carbonate bond (-O-C(O)-O-) have very short half-lives and poor plasma stability and adding a spacer of -C(O)-CH2-CH2-C(O)- would improve the stability of the conjugate, as taught by Kern, Teitelbaum and Varshosaz. One of ordinary skill in the art would have a reasonable expectation because 1) Bregeon teaches DBCO-NH-PEG4-Val-Cit-PAB-drug can be used for making ADCs for different antibodies and different drugs; 2) Kern and Varshosaz teach that budesonide-antibody conjugate can further improve therapeutic properties of budesonide; 3) direct link PAB and budesonide would form a carbonate bond (taught by Kern) and drug conjugates with a carbonate bond linker have poor plasma stability (taught by Kern and Teitelbaum), adding a spacer of -C(O)-CH2-CH2-C(O)- would improve the stability of the conjugate; 4) Varshosaz teaches inserting a carboxylic group at C21 of budesonide by succinic anhydride and the ester bond between the drug and the spacer and between the spacer and linker could be hydrolyzed by the esterases of the GI tract. Based on the teachings of the references, one of ordinary skill in the art would have a reasonable expectation to reach the elected species: DBCO-NH-PEG4-Val-Cit-PAB-spacer-budesonide, wherein the spacer is -C(O)-CH2-CH2-C(O)-, because this compound would have an enhanced stability and be useful to make a good antibody-budesonide conjugate with good stability and good activity for treating inflammatory condition in colon. The motivation would have been to expand the options for budesonide-antibody conjugates.
One of ordinary skill in the art would be motivated to modify the compounds of the reference patents based on the teachings of Bregeon, Kern, Teitelbaum, Varshosaz, and Lemke, to arrive at the instantly claimed compound (e.g. the elected compound of instant claim 76), wherein such a compound could be conjugated to an antibody as suggested by Bregeon, in order to facilitate targeted delivery of the steroid payload to target cells, targeted by the antibody, which would be useful in the treatment of, for example, immunological diseases in colon as taught by Kern, Teitelbaum, and Varshosaz.
Similarly, claims 2, 3, 7-9, 52, 64, 65, 68-71, 73, and 76 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the copending Application Nos. (reference applications) listed below in view of Bregeon (Bregeon et al., Pub. No.: US 2015/0165064 A1, Publication Date: 06-18-2015, cited in IDS of 08/23/2024), Kern (Kern et al., Bioconjugate Chem. 2016, 27, 2081-2088, Publication Date: 07-28-2016, cited in IDS of 08/23/2024), Teitelbaum (Teitelbaum et al., Bioorg. Med. Chem., 21 (2013) 5605-5617, Publication Date: 05/24/2013), and Varshosaz (Varshosaz et al., International Journal of Pharmaceutics, 365, (2009) 69-76, Publication Date: 08/30/2008, cited in IDS of 08/23/2024) for the instant claims 2, 3, 8-9, 52, 64, 65, 68-71, 73, and 76, and further in view of Lemke (Lemke et al., Foye’s Principles of Medicinal Chemistry, Chapter 44, pp. 1253, Publication Year: 2008, cited in IDS of 08/23/2024) for the instant claim 7.
Appl. No.
Brief Description of the Invention
Pertinent Claims
17612204
Steroid Compounds and Conjugates Thereof
1, 35, 90, 94-114, 145
18670314
Steroid Compounds and Conjugates Thereof
2-4, 7-9, 12,15, 26, 29, 33, 44, 46, 52, 64, 65, 68-73, 76-83, 88, 91-95
19201075
Steroid Compounds and Conjugates Thereof
39, 43-46, 51-60
Claims 2, 3, 7-9, 52, 64, 65, 68-71, 73, and 76 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 rejection, the 103 being incorporated here. The addition of the patented claims of the reference patent over related subject matter only further supports this obviousness.
It is specifically noted that all the above-listed reference applications are drawn to steroid compounds and linker/spacer conjugate thereof, wherein the steroid compounds all have similar/overlapping structures with those of the reference patent 11,760,775 as presented above. However, it is noted that the reference applications do not specifically disclose the elected compound of the instant invention, which can be considered as the intermediate product for making ADCs of the reference patent, particularly with regard to the budesonide, SP structure of the elected species, and/or R4 in the R-configuration. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
The above-listed reference applications, Bregeon, Kern, Teitelbaum, Varshosaz and Lemke are considered to be analogous to the present invention as they are in the same field of biologically active compounds/agents and their modification for improved delivery/efficacy. Thus, it would have been obvious to one of ordinary skill in the art that the compounds of the reference application claims could be modified to make the precursor of an ADC: DBCO-NH-PEG4-Val-Cit-PAB-drug (e.g. DBCO-NH-PEG4-Val-Cit-PAB-MMAE) as taught by Bregeon, and to replace the MMAE with budesonide and to add a spacer of -C(O)-CH2-CH2-C(O)- between PAB and budesonide through ester bonds, because the carbonate bond (-O-C(O)-O-) have very short half-lives and poor plasma stability and adding a spacer of -C(O)-CH2-CH2-C(O)- would improve the stability of the conjugate, as taught by Kern, Teitelbaum and Varshosaz. One of ordinary skill in the art would have a reasonable expectation because 1) Bregeon teaches DBCO-NH-PEG4-Val-Cit-PAB-drug can be used for making ADCs for different antibodies and different drugs with precise linkage to multiple antibodies; 2) Kern and Varshosaz teach that budesonide-antibody conjugate can further improve therapeutic properties of budesonide; 3) direct link PAB and budesonide would form a carbonate bond (taught by Kern) and drug conjugates with a carbonate bond linker have poor plasma stability (taught by Teitelbaum); 4) Varshosaz teaches inserting a carboxylic group at C21 of budesonide by succinic anhydride and the ester bond between the drug and the spacer and between the spacer and linker could be hydrolyzed by the esterases of the GI tract. Based on the teachings of the references, one of ordinary skill in the art would have a reasonable expectation to reach the elected species: DBCO-NH-PEG4-Val-Cit-PAB-spacer-budesonide, wherein the spacer is -C(O)-CH2-CH2-C(O)-, because this compound would have an improved stability and be useful to make a good antibody-budesonide conjugate with good stability and good activity for treating inflammatory condition in colon. The motivation would have been to expand the options for budesonide-antibody conjugates.
One of ordinary skill in the art would be motivated to modify the compounds of the reference applications based on the teachings of Bregeon, Kern, Teitelbaum, Varshosaz, and Lemke, to arrive at the instantly claimed compound (e.g. the elected compound of instant claim 76), wherein such a compound could be conjugated to an antibody as suggested by Bregeon, in order to facilitate targeted delivery of the steroid payload to target cells, targeted by the antibody, which would be useful in the treatment of, for example, immunological diseases in colon as taught by Kern, Teitelbaum, and Varshosaz.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/CHENG LU/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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