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 .
Status of the Claims
Claims 1, 2, 4, 5, 6, 8, 9, 14, 21, 23, 24, 26, 27, 28, 29, 30, 40, 44, 45, 51, 56, 61, 64, and 67-78 are pending. Claims 6, 68-71, and 76-78 are withdrawn. Claims 1, 2, 4, 5, 8, 9, 14, 21, 23, 24, 26, 27, 28, 29, 30, 40, 44, 45, 51, 56, 64, 67, and 72-75 are rejected. Claim 61 is objected to.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 9/12/2023 has been considered by the Examiner.
Election/Restrictions
Applicant’s election without traverse of Group I and the species A1:
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in the reply filed on 3/27/2026 is acknowledged.
Claims 1, 2, 4, 5, 8, 9, 14, 21, 23, 24, 26, 27, 28, 29, 30, 40, 44, 45, 51, 56, 61, 64, 67, and 72-75 embrace Applicant’s elected species and are therefore under examination. As per MPEP 803.02, the examiner will determine whether the entire scope of the claims is patentable. Applicants' elected species is allowable. Therefore, according to MPEP 803.02: should the elected species be found allowable, the examination of the Markush-type claim will be extended. If the examination is extended and a non-elected species found not allowable, the Markush-type claim shall be rejected and claims to the nonelected invention held withdrawn from further consideration. The examination of the Markush-type claims has been extended to include the species and combinations cited below under 35 USC 103, which are not allowable. Additionally, claim 61 has been searched in full and is free of the art.
As a non-elected species has been found not allowable, the Markush-type claims have been rejected and claims to the nonelected invention held withdrawn from further consideration.
Claims 6, 68-71 and 76-78 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Objections
Claim 61 is objected to because of the following informalities: Claim 61, p. 16, line 2 should end in “is selected from the group consisting of” and the last two structures on p. 26 and 27 should have an “and” between them. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 21 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 21 depends from claim 4 (which depends from claim 1) and recites the following:
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, wherein neither claim 21 nor claim 4 define such variables listed “as previously defined”. Examiner recommends that the variables shown supra be explicitly defined in claim 21. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 23 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 23 depends from claim 4 (which depends from claim 1) and recites the following:
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(p. 11), wherein neither claim 21 nor claim 4 define such variables listed “as previously defined”. Examiner recommends that the variables shown supra be explicitly defined in claim 23. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 24 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 24 depends from claim 1 and recites the following:
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(p. 12), wherein neither claim 24 nor claim 1 define such variables listed “as previously defined”. Examiner recommends that the variables shown supra be explicitly defined in claim 24. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 29 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 29 depends from claim 1 and recites the following:
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, wherein neither claim 29 nor claim 1 define such variables listed “as previously defined”. Examiner recommends that the variables shown supra be explicitly defined in claim 29. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
**In the interest of compact prosecution, the variables described supra for claims 21, 23, 24, and 29 were obtained from instant claims 5, 8, 14, and 28 to perform a full examination.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 24, 26, 29, 30, 44, 45, and 56 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 24, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 26 is rejected because it refers to Tables 1 or 2 of the instant specification. A claim should particularly point out and distinctly claim the subject matter which the applicant regards as his invention and, under modern claim practice, stand alone to define the invention. MPEP 2173.05(s) states “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)”. In the interest of compact prosecution, the Examiner has relied upon Tables 1 and 2 in the instant specification for examination.
Regarding claim 29, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 30, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 44, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 45 is additionally rejected for depending from claim 44 and failing to remedy its deficiencies.
In the last two lines of claim 56, it is recited “or fatty acid in Formula (I)” to describe the fatty acid structures shown above in the claim. It is unclear what is intended by a fatty acid being linked to another fatty acid wherein there is only one fatty acid in Formula (I). Examiner recommends clarifying this language.
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.
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.
Claim(s) 1, 2, 4, 5, 8, 9, 14, 21, 23, 24, 26, 27, 28, 29, 30, 40, 44, 45, 51, 64, 67, and 72-75 is/are rejected under 35 U.S.C. 103 as being unpatentable over Arista et al. (US11613543-eligible as art under 102(a)(2)), in view of Irby et al. (Mol. Pharmaceutics, 2017, 14, 1325-1338), and further in view of Banerjee et al. (Journal of Drug Delivery, 2012, 1-17) and Delahousse et al. (Cancer Chemotherapy and Pharmacology, 2019, 84: 937-958).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Arista teaches compounds for the treatment of disease (see abstract), wherein a specific compound taught is shown here:
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(see compound 31, column 157), and may be included in a pharmaceutical composition with one or more pharmaceutically acceptable carriers (see claim 9). Such diseases treated may be hairy cell leukemia (see column 2, line 4). Arista additionally discloses that the drugs of their invention may be used in combination with one or more therapeutically active agents (see claim 8). Arista fails to disclose the compound above linked to a fatty acid.
Irby teaches lipid-drug conjugate for enhancing drug delivery (see title). “Lipid-drug conjugates (LDCs) are drug molecules that have been covalently modified with lipids. LDCs have demonstrated several advantages including improved oral bioavailability, enhanced tumor targeting, reduced toxicity, and enhanced drug loading into delivery carriers” (see introduction, p. 1325). Lipids include fatty acids; see the following from left column of p. 1325:
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Both Arista and Irby fail to teach the linker which may include the instant “solubilizing domain”, which primary consists of a polyethylene glycol chain for the elected species. Banerjee teaches poly(ethylene glycol)-prodrug conjugates, concept, design and applications (see title). [The instant elected species “solubilizing domain” is comprised of polyethylene glycol.] “The objectives for designing a polymer therapeutics are primarily to improve the potential of the respective drug by (i) enhancing water solubility, particularly relevant for some drugs with low aqueous solubility, (ii) stability against degrading enzymes or reduced uptake by reticulo-endothelial system (RES), and (iii) targeted delivery of drugs to specific sides of action in the body” (see introduction, left column, p. 1). Banerjee specifically highlights the system in Figure 1:
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(see p. 2). “Poly(ethyleneglycol) (PEG) is the most commonly used nonionic polymer in the field of polymer-based drug delivery. Due to high aqueous solubility, PEG polymer is considered as a versatile candidate for the prodrug conjugation” (see introduction, left column, p. 1). Irby fails to disclose the specific linkers of the instant claims.
Delahousse teaches a study regarding prodrugs as a drug delivery system in oncology (see title). The choice of linker for the prodrug conjugation strategy is important and it should be cleavable so that the active drug can be liberated spontaneously or under triggerable conditions (see first full para. right column, p. 939). See Delahousse Table 1:
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.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art fails to disclose the instantly claimed bifunctional protein degrader attached to a fatty acid. Additional dependent limitations will be addressed below.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claims 1 and 2, it would have been obvious to attach the instantly claimed bifunctional protein degrader (compound above of the prior art identical to that of the bifunctional protein degrader of the elected species) to a fatty acid with a reasonable expectation of success at arriving a conjugate useful in the treatment of cancer (such as hairy cell leukemia). The (cleavable) linkers of the instant claims are well known in the art for drug conjugates and prodrugs. Additionally, regarding the solubilizing domain (part of ‘linker’ in claim 2), a skilled artisan would have been motivated to insert such a portion in order to increase water solubility of the drug (bifunctional protein degrader) and more effectively target the active site of interest. Regarding the fatty acid tail, lipids, including fatty acids, were known additions to better enhance drug delivery, including enhanced target site (tumor) delivery. A skilled artisan would have been motivated to add a fatty acid to a known drug in an effort to improve such drugs performance and disease fighting capabilities.
Regarding instant claims 4, 5, 8-9, 14, 21, 23-24, and 28-29, the targeting ligase binder of the prior art embraces the instant structure of:
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, wherein n = 1; Rd3 and Rd5 = H; p = 0; Ring A = 6 membered aryl substituted by C1 alkoxyl. Specifically regarding instant claim 8, the targeting ligase binder embraces the following instant formula:
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, wherein U = CH; Rd6 = C1 alkoxyl; n = 1. Regarding instant claim 14, the prior art shown supra (Delahousse) lists commonly used linkers for the instant technology. The prior art embraces the instant “L2”:
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, of the drug shown supra, highlighted here:
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, wherein X1, L2, X2 form a spiroheterocyclyl; L1 = C2 alkylene; L3 = C(O). Regarding instant claim 23, the prior art targeting ligase binder and L2 embrace the following:
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. Regarding instant claim 24, the prior art drug has the following structure:
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, wherein the instant targeting ligand is:
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. Regarding instant claim 28, the prior art targeting ligand embraces the instant claims:
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, wherein R3a = C1 alkyl; R2a and R4a = F; R1a and R5a = H. Regarding instant claim 29, the prior art whole structure embraces the instant:
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, as individually described above. Additionally, regarding instant claim 64, it would have been obvious to manufacture a pharmaceutical composition with at least one pharmaceutically acceptable carrier, as this was previous demonstrated successfully; regarding instant claim 67, combinations would also have been obvious based on prior art teachings.
Regarding instant claims 26 and 27, wherein the prior art structure has the same as that instantly claimed, it is inherent that it would bind identical targets.
Regarding instant claim 30, the prior art (Delahousse) teaches linkers that are esters. Regarding instant claim 40, the prior art shows the following as an example of a linker:
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, which embraces instant
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, wherein y = 0 and G = N-C1 alkyl.
Regarding instant claims 44 and 45, the solubilizing domain the applicant’s elected species is comprised of polyethylene glycol, which is a water-soluble polymer. Such linking components are described above and provide motivation for increase water solubility of a drug and improved targeted delivery. Regarding instant claim 51, applicant’s elected species’ solubilizing domain is the following formula:
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, comprised of polyethylene glycol as described supra.
Regarding instant claims 72-75, which all ultimately depend from the conjugate of instant claim 1 and are directed toward various uses of the claims, the use would be inherent for an obvious product (the instant conjugate). Therefore, “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979)”. Also, “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)”. See MPEP 2145(II). Therefore, claims 72-75 are also rejected under 35 USC 103 as being obvious.
Claim(s) 56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Arista et al. (US11613543-eligible as art under 102(a)(2)), in view of Irby et al. (Mol. Pharmaceutics, 2017, 14, 1325-1338), and further in view of Banerjee et al. (Journal of Drug Delivery, 2012, 1-17) and Delahousse et al. (Cancer Chemotherapy and Pharmacology, 2019, 84: 937-958), as applied to claims 1, 2, 4, 5, 8, 9, 14, 21, 23, 24, 26, 27, 28, 29, 30, 40, 44, 45, 51, 64, 67, and 72-75 above, and further in view of Usera et al. (WO2015006728).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
The prior art described supra fails to disclose a specific fatty acid of instant claim 56.
Usera describes conjugates and specifically discloses the following on p. 86:
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.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art does not have a single embodiment of an instantly described conjugate with the bifunctional protein degrader-L1-solubilizing domain-and specific fatty acid of instant claim 56.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claim 56, the prior art fatty acid component of the conjugate embraces the following structure:
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, wherein X = NH; R10 = H; p = 10; R1 = CH3; q= 10; R2 = COOH. As fatty acids were known to help direct targeted delivery of a drug, it would have been obvious to a PHOSITA to use a fatty acid that was successfully demonstrated in conjugate technology, with a reasonable expectation of success.
Claim(s) 1, 2, 4, 5, 8, 9, 14, 21, 23, 24, 26, 27, 28, 29, 30, 40, 44, 45, 51, 64, 67, and 72-75 is/are rejected under 35 U.S.C. 103 as being unpatentable over Arista et al. (US20210002285-eligible as art under 102(a)(2)), in view of Irby et al. (Mol. Pharmaceutics, 2017, 14, 1325-1338), and further in view of Banerjee et al. (Journal of Drug Delivery, 2012, 1-17) and Delahousse et al. (Cancer Chemotherapy and Pharmacology, 2019, 84: 937-958).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Arista teaches compounds for the treatment of disease (see abstract), wherein a specific compound taught is shown here:
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(see compound 31, para. [0934]), and may be included in a pharmaceutical composition with one or more pharmaceutically acceptable carriers (see claim 22). Such diseases treated may be hairy cell leukemia (see para. [0007]). Arista additionally discloses that the drugs of their invention may be used in combination with one or more therapeutically active agents (see claim 23). Arista fails to disclose the compound above linked to a fatty acid.
Irby teaches lipid-drug conjugate for enhancing drug delivery (see title). “Lipid-drug conjugates (LDCs) are drug molecules that have been covalently modified with lipids. LDCs have demonstrated several advantages including improved oral bioavailability, enhanced tumor targeting, reduced toxicity, and enhanced drug loading into delivery carriers” (see introduction, p. 1325). Lipids include fatty acids; see the following from left column of p. 1325:
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Both Arista and Irby fail to teach the linker which may include the instant “solubilizing domain”, which primary consists of a polyethylene glycol chain for the elected species. Banerjee teaches poly(ethylene glycol)-prodrug conjugates, concept, design and applications (see title). [The instant elected species “solubilizing domain” is comprised of polyethylene glycol.] “The objectives for designing a polymer therapeutics are primarily to improve the potential of the respective drug by (i) enhancing water solubility, particularly relevant for some drugs with low aqueous solubility, (ii) stability against degrading enzymes or reduced uptake by reticulo-endothelial system (RES), and (iii) targeted delivery of drugs to specific sides of action in the body” (see introduction, left column, p. 1). Banerjee specifically highlights the system in Figure 1:
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(see p. 2). “Poly(ethyleneglycol) (PEG) is the most commonly used nonionic polymer in the field of polymer-based drug delivery. Due to high aqueous solubility, PEG polymer is considered as a versatile candidate for the prodrug conjugation” (see introduction, left column, p. 1). Irby fails to disclose the specific linkers of the instant claims.
Delahousse teaches a study regarding prodrugs as a drug delivery system in oncology (see title). The choice of linker for the prodrug conjugation strategy is important and it should be cleavable so that the active drug can be liberated spontaneously or under triggerable conditions (see first full para. right column, p. 939). See Delahousse Table 1:
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.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art fails to disclose the instantly claimed bifunctional protein degrader attached to a fatty acid. Additional dependent limitations will be addressed below.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claims 1 and 2, it would have been obvious to attach the instantly claimed bifunctional protein degrader (compound above of the prior art identical to that of the bifunctional protein degrader of the elected species) to a fatty acid with a reasonable expectation of success at arriving a conjugate useful in the treatment of cancer (such as hairy cell leukemia). The (cleavable) linkers of the instant claims are well known in the art for drug conjugates and prodrugs. Additionally, regarding the solubilizing domain (part of ‘linker’ in claim 2), a skilled artisan would have been motivated to insert such a portion in order to increase water solubility of the drug (bifunctional protein degrader) and more effectively target the active site of interest. Regarding the fatty acid tail, lipids, including fatty acids, were known additions to better enhance drug delivery, including enhanced target site (tumor) delivery. A skilled artisan would have been motivated to add a fatty acid to a known drug in an effort to improve such drugs performance and disease fighting capabilities.
Regarding instant claims 4, 5, 8-9, 14, 21, 23-24, and 28-29, the targeting ligase binder of the prior art embraces the instant structure of:
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, wherein n = 1; Rd3 and Rd5 = H; p = 0; Ring A = 6 membered aryl substituted by C1 alkoxyl. Specifically regarding instant claim 8, the targeting ligase binder embraces the following instant formula:
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, wherein U = CH; Rd6 = C1 alkoxyl; n = 1. Regarding instant claim 14, the prior art shown supra (Delahousse) lists commonly used linkers for the instant technology. The prior art embraces the instant “L2”:
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, of the drug shown supra, highlighted here:
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, wherein X1, L2, X2 form a spiroheterocyclyl; L1 = C2 alkylene; L3 = C(O). Regarding instant claim 23, the prior art targeting ligase binder and L2 embrace the following:
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. Regarding instant claim 24, the prior art drug has the following structure:
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, wherein the instant targeting ligand is:
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. Regarding instant claim 28, the prior art targeting ligand embraces the instant claims:
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, wherein R3a = C1 alkyl; R2a and R4a = F; R1a and R5a = H. Regarding instant claim 29, the prior art whole structure embraces the instant:
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, as individually described above. Additionally, regarding instant claim 64, it would have been obvious to manufacture a pharmaceutical composition with at least one pharmaceutically acceptable carrier, as this was previous demonstrated successfully; regarding instant claim 67, combinations would also have been obvious based on prior art teachings.
Regarding instant claims 26 and 27, wherein the prior art structure has the same as that instantly claimed, it is inherent that it would bind identical targets.
Regarding instant claim 30, the prior art (Delahousse) teaches linkers that are esters. Regarding instant claim 40, the prior art shows the following as an example of a linker:
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, which embraces instant
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, wherein y = 0 and G = N-C1 alkyl.
Regarding instant claims 44 and 45, the solubilizing domain the applicant’s elected species is comprised of polyethylene glycol, which is a water-soluble polymer. Such linking components are described above and provide motivation for increase water solubility of a drug and improved targeted delivery. Regarding instant claim 51, applicant’s elected species’ solubilizing domain is the following formula:
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, comprised of polyethylene glycol as described supra.
Regarding instant claims 72-75, which all ultimately depend from the conjugate of instant claim 1 and are directed toward various uses of the claims, the use would be inherent for an obvious product (the instant conjugate). Therefore, “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979)”. Also, “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)”. See MPEP 2145(II). Therefore, claims 72-75 are also rejected under 35 USC 103 as being obvious.
Claim(s) 56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Arista et al. (US20210002285-eligible as art under 102(a)(2)), in view of Irby et al. (Mol. Pharmaceutics, 2017, 14, 1325-1338), and further in view of Banerjee et al. (Journal of Drug Delivery, 2012, 1-17) and Delahousse et al. (Cancer Chemotherapy and Pharmacology, 2019, 84: 937-958), as applied to claims 1, 2, 4, 5, 8, 9, 14, 21, 23, 24, 26, 27, 28, 29, 30, 40, 44, 45, 51, 64, 67, and 72-75 above, and further in view of Usera et al. (WO2015006728).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
The prior art described supra fails to disclose a specific fatty acid of instant claim 56.
Usera describes conjugates and specifically discloses the following on p. 86:
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.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art does not have a single embodiment of an instantly described conjugate with the bifunctional protein degrader-L1-solubilizing domain-and specific fatty acid of instant claim 56.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claim 56, the prior art fatty acid component of the conjugate embraces the following structure:
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, wherein X = NH; R10 = H; p = 10; R1 = CH3; q= 10; R2 = COOH. As fatty acids were known to help direct targeted delivery of a drug, it would have been obvious to a PHOSITA to use a fatty acid that was successfully demonstrated in conjugate technology, with a reasonable expectation of success.
Claim(s) 1, 2, 4, 5, 8, 9, 14, 21, 23, 24, 26, 27, 28, 29, 30, 40, 44, 45, 51, 64, 67, and 72-75 is/are rejected under 35 U.S.C. 103 as being unpatentable over Arista et al. (US12441733-eligible as art under 102(a)(2)), in view of Irby et al. (Mol. Pharmaceutics, 2017, 14, 1325-1338), and further in view of Banerjee et al. (Journal of Drug Delivery, 2012, 1-17) and Delahousse et al. (Cancer Chemotherapy and Pharmacology, 2019, 84: 937-958).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Arista teaches compounds for the treatment of disease (see abstract), wherein a specific compound taught is shown here:
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(bottom of column 19 to top of column 20) and may be included in a pharmaceutical composition with one or more pharmaceutically acceptable carriers (see column 5, lines 45-49). Such diseases treated may be hairy cell leukemia (see column 2, line 17). Arista additionally discloses that the drugs of their invention may be used in combination with one or more therapeutically active agents (see column 5, lines 50-54). Arista fails to disclose the compound above linked to a fatty acid.
Irby teaches lipid-drug conjugate for enhancing drug delivery (see title). “Lipid-drug conjugates (LDCs) are drug molecules that have been covalently modified with lipids. LDCs have demonstrated several advantages including improved oral bioavailability, enhanced tumor targeting, reduced toxicity, and enhanced drug loading into delivery carriers” (see introduction, p. 1325). Lipids include fatty acids; see the following from left column of p. 1325:
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Both Arista and Irby fail to teach the linker which may include the instant “solubilizing domain”, which primary consists of a polyethylene glycol chain for the elected species. Banerjee teaches poly(ethylene glycol)-prodrug conjugates, concept, design and applications (see title). [The instant elected species “solubilizing domain” is comprised of polyethylene glycol.] “The objectives for designing a polymer therapeutics are primarily to improve the potential of the respective drug by (i) enhancing water solubility, particularly relevant for some drugs with low aqueous solubility, (ii) stability against degrading enzymes or reduced uptake by reticulo-endothelial system (RES), and (iii) targeted delivery of drugs to specific sides of action in the body” (see introduction, left column, p. 1). Banerjee specifically highlights the system in Figure 1:
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(see p. 2). “Poly(ethyleneglycol) (PEG) is the most commonly used nonionic polymer in the field of polymer-based drug delivery. Due to high aqueous solubility, PEG polymer is considered as a versatile candidate for the prodrug conjugation” (see introduction, left column, p. 1). Irby fails to disclose the specific linkers of the instant claims.
Delahousse teaches a study regarding prodrugs as a drug delivery system in oncology (see title). The choice of linker for the prodrug conjugation strategy is important and it should be cleavable so that the active drug can be liberated spontaneously or under triggerable conditions (see first full para. right column, p. 939). See Delahousse Table 1:
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.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art fails to disclose the instantly claimed bifunctional protein degrader attached to a fatty acid. Additional dependent limitations will be addressed below.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claims 1 and 2, it would have been obvious to attach the instantly claimed bifunctional protein degrader (compound above of the prior art identical to that of the bifunctional protein degrader of the elected species) to a fatty acid with a reasonable expectation of success at arriving a conjugate useful in the treatment of cancer (such as hairy cell leukemia). The (cleavable) linkers of the instant claims are well known in the art for drug conjugates and prodrugs. Additionally, regarding the solubilizing domain (part of ‘linker’ in claim 2), a skilled artisan would have been motivated to insert such a portion in order to increase water solubility of the drug (bifunctional protein degrader) and more effectively target the active site of interest. Regarding the fatty acid tail, lipids, including fatty acids, were known additions to better enhance drug delivery, including enhanced target site (tumor) delivery. A skilled artisan would have been motivated to add a fatty acid to a known drug in an effort to improve such drugs performance and disease fighting capabilities.
Regarding instant claims 4, 5, 8-9, 14, 21, 23-24, and 28-29, the targeting ligase binder of the prior art embraces the instant structure of:
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, wherein n = 1; Rd3 and Rd5 = H; p = 0; Ring A = 6 membered aryl substituted by C1 alkoxyl. Specifically regarding instant claim 8, the targeting ligase binder embraces the following instant formula:
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, wherein U = CH; Rd6 = C1 alkoxyl; n = 1. Regarding instant claim 14, the prior art shown supra (Delahousse) lists commonly used linkers for the instant technology. The prior art embraces the instant “L2”:
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, of the drug shown supra, highlighted here:
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, wherein X1, L2, X2 form a spiroheterocyclyl; L1 = C2 alkylene; L3 = C(O). Regarding instant claim 23, the prior art targeting ligase binder and L2 embrace the following:
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. Regarding instant claim 24, the prior art drug has the following structure:
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, wherein the instant targeting ligand is:
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. Regarding instant claim 28, the prior art targeting ligand embraces the instant claims:
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, wherein R3a = C1 alkyl; R2a and R4a = F; R1a and R5a = H. Regarding instant claim 29, the prior art whole structure embraces the instant:
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, as individually described above. Additionally, regarding instant claim 64, it would have been obvious to manufacture a pharmaceutical composition with at least one pharmaceutically acceptable carrier, as this was previous demonstrated successfully; regarding instant claim 67, combinations would also have been obvious based on prior art teachings.
Regarding instant claims 26 and 27, wherein the prior art structure has the same as that instantly claimed, it is inherent that it would bind identical targets.
Regarding instant claim 30, the prior art (Delahousse) teaches linkers that are esters. Regarding instant claim 40, the prior art shows the following as an example of a linker:
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, which embraces instant
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, wherein y = 0 and G = N-C1 alkyl.
Regarding instant claims 44 and 45, the solubilizing domain the applicant’s elected species is comprised of polyethylene glycol, which is a water-soluble polymer. Such linking components are described above and provide motivation for increase water solubility of a drug and improved targeted delivery. Regarding instant claim 51, applicant’s elected species’ solubilizing domain is the following formula:
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, comprised of polyethylene glycol as described supra.
Regarding instant claims 72-75, which all ultimately depend from the conjugate of instant claim 1 and are directed toward various uses of the claims, the use would be inherent for an obvious product (the instant conjugate). Therefore, “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979)”. Also, “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)”. See MPEP 2145(II). Therefore, claims 72-75 are also rejected under 35 USC 103 as being obvious.
Claim(s) 56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Arista et al. (US12441733-eligible as art under 102(a)(2)), in view of Irby et al. (Mol. Pharmaceutics, 2017, 14, 1325-1338), and further in view of Banerjee et al. (Journal of Drug Delivery, 2012, 1-17) and Delahousse et al. (Cancer Chemotherapy and Pharmacology, 2019, 84: 937-958), as applied to claims 1, 2, 4, 5, 8, 9, 14, 21, 23, 24, 26, 27, 28, 29, 30, 40, 44, 45, 51, 64, 67, and 72-75 above, and further in view of Usera et al. (WO2015006728).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
The prior art described supra fails to disclose a specific fatty acid of instant claim 56.
Usera describes conjugates and specifically discloses the following on p. 86:
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.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art does not have a single embodiment of an instantly described conjugate with the bifunctional protein degrader-L1-solubilizing domain-and specific fatty acid of instant claim 56.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claim 56, the prior art fatty acid component of the conjugate embraces the following structure:
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, wherein X = NH; R10 = H; p = 10; R1 = CH3; q= 10; R2 = COOH. As fatty acids were known to help direct targeted delivery of a drug, it would have been obvious to a PHOSITA to use a fatty acid that was successfully demonstrated in conjugate technology, with a reasonable expectation of success.
Claim(s) 1, 2, 4, 5, 8, 9, 14, 21, 23, 24, 26, 27, 28, 29, 30, 40, 44, 45, 51, 64, 67, and 72-75 is/are rejected under 35 U.S.C. 103 as being unpatentable over Arista et al. (US20240158399-eligible as art under 102(a)(2)), in view of Irby et al. (Mol. Pharmaceutics, 2017, 14, 1325-1338), and further in view of Banerjee et al. (Journal of Drug Delivery, 2012, 1-17) and Delahousse et al. (Cancer Chemotherapy and Pharmacology, 2019, 84: 937-958).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Arista teaches compounds for the treatment of disease (see abstract), wherein a specific compound taught is shown here:
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(see para. [0161]) and may be included in a pharmaceutical composition with one or more pharmaceutically acceptable carriers (see para. [0045]). Such diseases treated may be hairy cell leukemia (see para. [0011]). Arista additionally discloses that the drugs of their invention may be used in combination with one or more therapeutically active agents (see para. [0046]). Arista fails to disclose the compound above linked to a fatty acid.
Irby teaches lipid-drug conjugate for enhancing drug delivery (see title). “Lipid-drug conjugates (LDCs) are drug molecules that have been covalently modified with lipids. LDCs have demonstrated several advantages including improved oral bioavailability, enhanced tumor targeting, reduced toxicity, and enhanced drug loading into delivery carriers” (see introduction, p. 1325). Lipids include fatty acids; see the following from left column of p. 1325:
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Both Arista and Irby fail to teach the linker which may include the instant “solubilizing domain”, which primary consists of a polyethylene glycol chain for the elected species. Banerjee teaches poly(ethylene glycol)-prodrug conjugates, concept, design and applications (see title). [The instant elected species “solubilizing domain” is comprised of polyethylene glycol.] “The objectives for designing a polymer therapeutics are primarily to improve the potential of the respective drug by (i) enhancing water solubility, particularly relevant for some drugs with low aqueous solubility, (ii) stability against degrading enzymes or reduced uptake by reticulo-endothelial system (RES), and (iii) targeted delivery of drugs to specific sides of action in the body” (see introduction, left column, p. 1). Banerjee specifically highlights the system in Figure 1:
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(see p. 2). “Poly(ethyleneglycol) (PEG) is the most commonly used nonionic polymer in the field of polymer-based drug delivery. Due to high aqueous solubility, PEG polymer is considered as a versatile candidate for the prodrug conjugation” (see introduction, left column, p. 1). Irby fails to disclose the specific linkers of the instant claims.
Delahousse teaches a study regarding prodrugs as a drug delivery system in oncology (see title). The choice of linker for the prodrug conjugation strategy is important and it should be cleavable so that the active drug can be liberated spontaneously or under triggerable conditions (see first full para. right column, p. 939). See Delahousse Table 1:
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.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art fails to disclose the instantly claimed bifunctional protein degrader attached to a fatty acid. Additional dependent limitations will be addressed below.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claims 1 and 2, it would have been obvious to attach the instantly claimed bifunctional protein degrader (compound above of the prior art identical to that of the bifunctional protein degrader of the elected species) to a fatty acid with a reasonable expectation of success at arriving a conjugate useful in the treatment of cancer (such as hairy cell leukemia). The (cleavable) linkers of the instant claims are well known in the art for drug conjugates and prodrugs. Additionally, regarding the solubilizing domain (part of ‘linker’ in claim 2), a skilled artisan would have been motivated to insert such a portion in order to increase water solubility of the drug (bifunctional protein degrader) and more effectively target the active site of interest. Regarding the fatty acid tail, lipids, including fatty acids, were known additions to better enhance drug delivery, including enhanced target site (tumor) delivery. A skilled artisan would have been motivated to add a fatty acid to a known drug in an effort to improve such drugs performance and disease fighting capabilities.
Regarding instant claims 4, 5, 8-9, 14, 21, 23-24, and 28-29, the targeting ligase binder of the prior art embraces the instant structure of:
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, wherein n = 1; Rd3 and Rd5 = H; p = 0; Ring A = 6 membered aryl substituted by C1 alkoxyl. Specifically regarding instant claim 8, the targeting ligase binder embraces the following instant formula:
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, wherein U = CH; Rd6 = C1 alkoxyl; n = 1. Regarding instant claim 14, the prior art shown supra (Delahousse) lists commonly used linkers for the instant technology. The prior art embraces the instant “L2”:
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, of the drug shown supra, highlighted here:
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, wherein X1, L2, X2 form a spiroheterocyclyl; L1 = C2 alkylene; L3 = C(O). Regarding instant claim 23, the prior art targeting ligase binder and L2 embrace the following:
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. Regarding instant claim 24, the prior art drug has the following structure:
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, wherein the instant targeting ligand is:
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. Regarding instant claim 28, the prior art targeting ligand embraces the instant claims:
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, wherein R3a = C1 alkyl; R2a and R4a = F; R1a and R5a = H. Regarding instant claim 29, the prior art whole structure embraces the instant:
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, as individually described above. Additionally, regarding instant claim 64, it would have been obvious to manufacture a pharmaceutical composition with at least one pharmaceutically acceptable carrier, as this was previous demonstrated successfully; regarding instant claim 67, combinations would also have been obvious based on prior art teachings.
Regarding instant claims 26 and 27, wherein the prior art structure has the same as that instantly claimed, it is inherent that it would bind identical targets.
Regarding instant claim 30, the prior art (Delahousse) teaches linkers that are esters. Regarding instant claim 40, the prior art shows the following as an example of a linker:
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, which embraces instant
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, wherein y = 0 and G = N-C1 alkyl.
Regarding instant claims 44 and 45, the solubilizing domain the applicant’s elected species is comprised of polyethylene glycol, which is a water-soluble polymer. Such linking components are described above and provide motivation for increase water solubility of a drug and improved targeted delivery. Regarding instant claim 51, applicant’s elected species’ solubilizing domain is the following formula:
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, comprised of polyethylene glycol as described supra.
Regarding instant claims 72-75, which all ultimately depend from the conjugate of instant claim 1 and are directed toward various uses of the claims, the use would be inherent for an obvious product (the instant conjugate). Therefore, “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979)”. Also, “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)”. See MPEP 2145(II). Therefore, claims 72-75 are also rejected under 35 USC 103 as being obvious.
Claim(s) 56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Arista et al. (US20240158399-eligible as art under 102(a)(2)), in view of Irby et al. (Mol. Pharmaceutics, 2017, 14, 1325-1338), and further in view of Banerjee et al. (Journal of Drug Delivery, 2012, 1-17) and Delahousse et al. (Cancer Chemotherapy and Pharmacology, 2019, 84: 937-958), as applied to claims 1, 2, 4, 5, 8, 9, 14, 21, 23, 24, 26, 27, 28, 29, 30, 40, 44, 45, 51, 64, 67, and 72-75 above, and further in view of Usera et al. (WO2015006728).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
The prior art described supra fails to disclose a specific fatty acid of instant claim 56.
Usera describes conjugates and specifically discloses the following on p. 86:
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.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art does not have a single embodiment of an instantly described conjugate with the bifunctional protein degrader-L1-solubilizing domain-and specific fatty acid of instant claim 56.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claim 56, the prior art fatty acid component of the conjugate embraces the following structure:
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, wherein X = NH; R10 = H; p = 10; R1 = CH3; q= 10; R2 = COOH. As fatty acids were known to help direct targeted delivery of a drug, it would have been obvious to a PHOSITA to use a fatty acid that was successfully demonstrated in conjugate technology, with a reasonable expectation of success.
Claim(s) 1, 2, 4, 14, 26, 27, 30, 40, 44, 45, 64, 67, and 72-75 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gray et al. (WO2019148150), in view of Irby et al. (Mol. Pharmaceutics, 2017, 14, 1325-1338), and further in view of Banerjee et al. (Journal of Drug Delivery, 2012, 1-17) and Delahousse et al. (Cancer Chemotherapy and Pharmacology, 2019, 84: 937-958).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Gray teaches the following bifunctional compound:
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(see p. 2). A specific example of the bifunctional compounds taught by Gray is shown here from the top of p. 127 (arrow added by Examiner, pointing to linker):
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.
Gray fails to disclose the compound above linked to a fatty acid. Gray’s bifunctional compound by be included with a carrier and also may be used in combination with a second agent in the use of treating cancer (see p. 161, lines 24-31).
Irby teaches lipid-drug conjugate for enhancing drug delivery (see title). “Lipid-drug conjugates (LDCs) are drug molecules that have been covalently modified with lipids. LDCs have demonstrated several advantages including improved oral bioavailability, enhanced tumor targeting, reduced toxicity, and enhanced drug loading into delivery carriers” (see introduction, p. 1325). Lipids include fatty acids; see the following from left column of p. 1325:
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Both Gray and Irby fail to teach the linker which may include the instant “solubilizing domain”, which primary consists of a polyethylene glycol chain for the elected species. Banerjee teaches poly(ethylene glycol)-prodrug conjugates, concept, design and applications (see title). [The instant elected species “solubilizing domain” is comprised of polyethylene glycol.] “The objectives for designing a polymer therapeutics are primarily to improve the potential of the respective drug by (i) enhancing water solubility, particularly relevant for some drugs with low aqueous solubility, (ii) stability against degrading enzymes or reduced uptake by reticulo-endothelial system (RES), and (iii) targeted delivery of drugs to specific sides of action in the body” (see introduction, left column, p. 1). Banerjee specifically highlights the system in Figure 1:
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(see p. 2). “Poly(ethyleneglycol) (PEG) is the most commonly used nonionic polymer in the field of polymer-based drug delivery. Due to high aqueous solubility, PEG polymer is considered as a versatile candidate for the prodrug conjugation” (see introduction, left column, p. 1). Irby fails to disclose the specific linkers of the instant claims.
Delahousse teaches a study regarding prodrugs as a drug delivery system in oncology (see title). The choice of linker for the prodrug conjugation strategy is important and it should be cleavable so that the active drug can be liberated spontaneously or under triggerable conditions (see first full para. right column, p. 939). See Delahousse Table 1:
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.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art fails to disclose the instantly claimed bifunctional protein degrader attached to a fatty acid. Additional dependent limitations will be addressed below.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claims 1, 2, 4, 64, and 67, it would have been obvious to attach the instantly claimed bifunctional protein degrader to a fatty acid with a reasonable expectation of success at arriving a conjugate (with a carrier and/or additionally therapeutic active) useful in the treatment of cancer. The instantly claimed bifunctional protein degrader, as broken down in claim 4:
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aligns with the functionality of the bifunctional compound of the prior art. The (cleavable) linkers of the instant claims are well known in the art for drug conjugates and prodrugs. Additionally, regarding the solubilizing domain (part of ‘linker’ in claim 2), a skilled artisan would have been motivated to insert such a portion in order to increase water solubility of the drug (bifunctional protein degrader) and more effectively target the active site of interest. Regarding the fatty acid tail, lipids, including fatty acids, were known additions to better enhance drug delivery, including enhanced target site (tumor) delivery. A skilled artisan would have been motivated to add a fatty acid to a known drug in an effort to improve such drugs performance and disease fighting capabilities.
Regarding instant claim 14, the linker highlighted with the arrow supra is embraced by an instant linker of
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, wherein L1 = C3-8 alkylene; X1 and X2 = bond; L2 = C2 alkylene; L3 = NH.
Regarding instant claims 26 and 27, wherein the prior art has the same design as claim 4, the functionality of such targeting ligand is inherent. Additionally, Gray teaches that the compounds act as protein degradation including moieties for BTK (see abstract). Regarding instant claim 30, it is common to have esters as cleavable linkers in conjugate technology. Regarding instant claim 40, the prior art shows the following as an example of a linker:
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, which embraces instant
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, wherein y = 0 and G = N-C1 alkyl.
Regarding instant claims 44 and 45, the solubilizing domain the applicant’s elected species is comprised of polyethylene glycol, which is a water-soluble polymer. Such linking components are described above and provide motivation for increase water solubility of a drug and improved targeted delivery.
Regarding instant claims 72-75, which all ultimately depend from the conjugate of instant claim 1 and are directed toward various uses of the claims, the use would be inherent for an obvious product (the instant conjugate). Therefore, “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979)”. Also, “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)”. See MPEP 2145(II). Therefore, claims 72-75 are also rejected under 35 USC 103 as being obvious.
Claim(s) 56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gray et al. (WO2019148150), in view of Irby et al. (Mol. Pharmaceutics, 2017, 14, 1325-1338), and further in view of Banerjee et al. (Journal of Drug Delivery, 2012, 1-17) and Delahousse et al. (Cancer Chemotherapy and Pharmacology, 2019, 84: 937-958), as applied to claims 1, 2, 4, 14, 26, 27, 30, 40, 44, 45, 64, 67, and 72-75 above, and further in view of Usera et al. (WO2015006728).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
The prior art described supra fails to disclose a specific fatty acid of instant claim 56.
Usera describes conjugates and specifically discloses the following on p. 86:
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.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art does not have a single embodiment of an instantly described conjugate with the bifunctional protein degrader-L1-solubilizing domain-and specific fatty acid of instant claim 56.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Regarding instant claim 56, the prior art fatty acid component of the conjugate embraces the following structure:
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, wherein X = NH; R10 = H; p = 10; R1 = CH3; q= 10; R2 = COOH. As fatty acids were known to help direct targeted delivery of a drug, it would have been obvious to a PHOSITA to use a fatty acid that was successfully demonstrated in conjugate technology, with a reasonable expectation of success.
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, 4, 5, 8, 9, 14, 21, 23, 24, 26, 27, 28, 29, 30, 40, 44, 45, 51, 56, 64, 67, and 72-75 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11613543 in view of Irby et al. (Mol. Pharmaceutics, 2017, 14, 1325-1338), and further in view of Banerjee et al. (Journal of Drug Delivery, 2012, 1-17), Delahousse et al. (Cancer Chemotherapy and Pharmacology, 2019, 84: 937-958), and Usera et al. (WO2015006728).
Arista teaches compounds for the treatment of disease (see claims 1 and 10), wherein a specific compound taught is shown here:
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(see claim 7, bottom of column 195), and may be included in a pharmaceutical composition with one or more pharmaceutically acceptable carriers (see claim 9). Such diseases treated may be hairy cell leukemia (see claim 14). Arista additionally discloses that the drugs of their invention may be used in combination with one or more therapeutically active agents (see claim 8). Arista fails to disclose the compound above linked to a fatty acid.
Irby teaches lipid-drug conjugate for enhancing drug delivery (see title). “Lipid-drug conjugates (LDCs) are drug molecules that have been covalently modified with lipids. LDCs have demonstrated several advantages including improved oral bioavailability, enhanced tumor targeting, reduced toxicity, and enhanced drug loading into delivery carriers” (see introduction, p. 1325). Lipids include fatty acids; see the following from left column of p. 1325:
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Both Arista and Irby fail to teach the linker which may include the instant “solubilizing domain”, which primary consists of a polyethylene glycol chain for the elected species. Banerjee teaches poly(ethylene glycol)-prodrug conjugates, concept, design and applications (see title). [The instant elected species “solubilizing domain” is comprised of polyethylene glycol.] “The objectives for designing a polymer therapeutics are primarily to improve the potential of the respective drug by (i) enhancing water solubility, particularly relevant for some drugs with low aqueous solubility, (ii) stability against degrading enzymes or reduced uptake by reticulo-endothelial system (RES), and (iii) targeted delivery of drugs to specific sides of action in the body” (see introduction, left column, p. 1). Banerjee specifically highlights the system in Figure 1:
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(see p. 2). “Poly(ethyleneglycol) (PEG) is the most commonly used nonionic polymer in the field of polymer-based drug delivery. Due to high aqueous solubility, PEG polymer is considered as a versatile candidate for the prodrug conjugation” (see introduction, left column, p. 1). Irby fails to disclose the specific linkers of the instant claims.
Delahousse teaches a study regarding prodrugs as a drug delivery system in oncology (see title). The choice of linker for the prodrug conjugation strategy is important and it should be cleavable so that the active drug can be liberated spontaneously or under triggerable conditions (see first full para. right column, p. 939). See Delahousse Table 1:
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.
The prior art described supra fails to disclose a specific fatty acid of instant claim 56.
Usera describes conjugates and specifically discloses the following on p. 86:
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.
Regarding instant claims 1 and 2, it would have been obvious to attach the instantly claimed bifunctional protein degrader (compound above of the prior art identical to that of the bifunctional protein degrader of the elected species) to a fatty acid with a reasonable expectation of success at arriving a conjugate useful in the treatment of cancer (such as hairy cell leukemia). The (cleavable) linkers of the instant claims are well known in the art for drug conjugates and prodrugs. Additionally, regarding the solubilizing domain (part of ‘linker’ in claim 2), a skilled artisan would have been motivated to insert such a portion in order to increase water solubility of the drug (bifunctional protein degrader) and more effectively target the active site of interest. Regarding the fatty acid tail, lipids, including fatty acids, were known additions to better enhance drug delivery, including enhanced target site (tumor) delivery. A skilled artisan would have been motivated to add a fatty acid to a known drug in an effort to improve such drugs performance and disease fighting capabilities.
Regarding instant claims 4, 5, 8-9, 14, 21, 23-24, and 28-29, the targeting ligase binder of the prior art embraces the instant structure of:
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, wherein n = 1; Rd3 and Rd5 = H; p = 0; Ring A = 6 membered aryl substituted by C1 alkoxyl. Specifically regarding instant claim 8, the targeting ligase binder embraces the following instant formula:
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, wherein U = CH; Rd6 = C1 alkoxyl; n = 1. Regarding instant claim 14, the prior art shown supra (Delahousse) lists commonly used linkers for the instant technology. The prior art embraces the instant “L2”:
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, of the drug shown supra, highlighted here:
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, wherein X1, L2, X2 form a spiroheterocyclyl; L1 = C2 alkylene; L3 = C(O). Regarding instant claim 23, the prior art targeting ligase binder and L2 embrace the following:
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. Regarding instant claim 24, the prior art drug has the following structure:
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, wherein the instant targeting ligand is:
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. Regarding instant claim 28, the prior art targeting ligand embraces the instant claims:
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, wherein R3a = C1 alkyl; R2a and R4a = F; R1a and R5a = H. Regarding instant claim 29, the prior art whole structure embraces the instant:
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, as individually described above. Additionally, regarding instant claim 64, it would have been obvious to manufacture a pharmaceutical composition with at least one pharmaceutically acceptable carrier, as this was previous demonstrated successfully; regarding instant claim 67, combinations would also have been obvious based on prior art teachings.
Regarding instant claims 26 and 27, wherein the prior art structure has the same as that instantly claimed, it is inherent that it would bind identical targets.
Regarding instant claim 30, the prior art (Delahousse) teaches linkers that are esters. Regarding instant claim 40, the prior art shows the following as an example of a linker:
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, which embraces instant
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, wherein y = 0 and G = N-C1 alkyl.
Regarding instant claims 44 and 45, the solubilizing domain the applicant’s elected species is comprised of polyethylene glycol, which is a water-soluble polymer. Such linking components are described above and provide motivation for increase water solubility of a drug and improved targeted delivery. Regarding instant claim 51, applicant’s elected species’ solubilizing domain is the following formula:
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, comprised of polyethylene glycol as described supra.
Regarding instant claims 72-75, which all ultimately depend from the conjugate of instant claim 1 and are directed toward various uses of the claims, the use would be inherent for an obvious product (the instant conjugate). Therefore, “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979)”. Also, “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)”. See MPEP 2145(II).
Regarding instant claim 56, the prior art fatty acid component of the conjugate embraces the following structure:
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, wherein X = NH; R10 = H; p = 10; R1 = CH3; q= 10; R2 = COOH. As fatty acids were known to help direct targeted delivery of a drug, it would have been obvious to a PHOSITA to use a fatty acid that was successfully demonstrated in conjugate technology, with a reasonable expectation of success.
Conclusion
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/MEGHAN C HEASLEY/Examiner, Art Unit 1626
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