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 .
Claims 47 and 49-66 are under consideration.
Rejections Maintained
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.
Claim(s) 47 and 49-55 and 58-64 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bhakta (Bhakta, et al., WO 2016/040856 A2; Published 03/17/2016, of record) in view of Buckley (Buckley, et al., Angew Chem Int Ed Engl 2014 53(9):2312, of record), Ali (Ali, et al., Journal of Mammary Gland Biology and Neoplasia 2000 Vol. 5 No. 3, of record), Pluta, (Pluta, et al., Neoplasma 2015 62:666, of record ), Jain (Jain et al., Pharm. Res 2015 32:3526, of record) and Chen (Chen, et al., WO 2015/071393 A1; Published 03/21/2015, of record).
Bhakta teaches on the subject of cystine engineered antibody drug conjugates (Bhakta, Abstract). Bhakta teaches that antibodies with cystine substations can be conjugated via the engineered thiol groups to produce ADCs with the goal being a uniform stoichiometry of 2 drugs per antibody (same as DAR = 2) in a homogeneous and site-specific conjugation scheme (Bhakta, ¶ 0009). Bhakta teaches that the ADC of Bhakta can is present in a pharmaceutical formulation further comprising pharmaceutically acceptable excipients (Bhakta, ¶ 00445). Bhakta teaches that the conjugate of Bhakta comprises an anti-HER2 antibody (Bhakta, ¶ 0020). Bhakta teaches that the disease to be treated is breast cancer (Bhakta, ¶ 00454) and that HER 2 is overexpressed in certain human breast cancers (Bhakta, ¶ 00526). Bhakta teaches that the conjugate structure of the ADC of Bhakta is maleimidocaproyl valine citrulline para-amino benzyl-MMAE (same as Ab-MC-vc-PAB-MMAE; which is the same as the conjugate structure of claim 47 except with MMAE as the drug instead of the PROTAC of claim 47 as the drug) (Bhakta, Claim 46).
Bhakta does not teach that that the drug moiety of the conjugate is a PROTAC having the structure E3LB-L2-PB, wherein E3LB is the tetrahydro-benzodiazepinone depicted in claim 47, L2 is a PEG2 moiety and PB is an estrogen receptor α (ERα) binding ligand.
Buckley teaches that PROTACs are heterobifunctional molecules that contain a ligand for an E3 ligase, a linker and a ligand that is to be targeted for degradation (Buckley, p 9, ¶ 3). Buckley teaches that this molecule can bind to both the E3 ligase and the target, inducing the formation of a ternary complex and that this “hijacking” E3 ligase can then lead to the polyubiquitination of the target protein, followed by its degradation by the proteasome (Buckley, p 9, ¶ 3). Buckley also teaches that E3 ligase inhibitors targeting XIAP were some of the first E3 ligase inhibitors discovered (Buckley, p 14, ¶ 3). Buckley teaches that there is a strong desire to develop PROTACs using small molecule ligands (as opposed to peptidic ligands, which are less drug-like and less stable than small molecules) to target E3 ligases such as cIAP1 and MDM2 (Buckley, p 10, ¶ 3). Regarding the specific E3 ligase to be used, cIAP1 is a member of the IAP genus, of which XIAP1 is also a member. Moreover, both cIAP1 and XIAP1 are species within the E3 ligase genus. Buckley teaches that PROTACs have advantages over other interventions, such as inhibitors, namely: 1) PROTACs do not need to inhibit interactions that occur over large surface areas; instead methods such as PROTACs require only a ligand capable of binding to the target protein to induce degradation and 2) unlike antagonists and inhibitors, which only control specific activities of their targets, PROTACs lead to degradation of the target protein and, thus, of function of other activities (such as scaffolding) (Buckley, p 9, ¶ 1).
Ali teaches that over half of breast cancers overexpress ERa and that around 70% of these cancers respond to inhibition with anti-estrogens such as tamoxifen (Ali, Abstract). Ali teaches that some ERa positive tumors are resistant to endocrine therapy and that this problem of resistance has resulted in the search for and the development of diverse hormonal therapies designed to inhibit ERa.
Pluta teaches that both XIAP1 and cIAP-1 were detected in 99% of breast cancer samples assayed (Pluta, p 669, Table 2).
Chen teaches on the subject of tetrahydro-benzodiazepinones (Chen, Abstract). Chen teaches that the tetrahydro-benzodiazepinones of Chen bind both XIAP and cIAP (Chen, p 1, ¶ 2). Chen teaches that the tetrahydro-benzodiazepinones of Chen are of Formula I’ (Chen, p 7, ¶ 2):
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Chen also teaches that the allowable variable groups for Formula I’ (R1, R2, R3, R4, R5, R9, W, X and Z) are the same as the corresponding variable groups for the XIAP binding moiety of claim 47 (Chen, p 7-p 9).
Jain teaches that hydrophobicity in linkers is problematic due to its propensity to cause aggregation, that PEG linkers can attenuate this effect and that ADCs comprising PEG4 linkers were markedly more effective than hydrocarbon linkers of the same length (Jain, p 3535, ¶ 2).
It would be prima facie obvious to one of ordinary skill in the art to combine the cystine engineered anti-HER2 ADC of Bhakta with the PROTAC technology taught by Buckley, the XIAP binding moiety taught by Chen and a PEG2 linker that is similar to the PEG4 linker taught by Jain. The net result of this combination would be the cystine engineered anti-HER2 ADC of Bhakta with the drug moiety replaced with a PROTAC comprising the XIAP binding moiety of Chen and an ERa binding ligand, wherein the XIAP binding moiety and the binding ligand are linked by a PEG2 linker and to use the resultant PROTAC antibody conjugate in a method of treating HER2 positive breast cancer. The motivation for making such a combination is to create an ADC that can be used to treat breast cancer by selectively targeting ERa for degradation through the use of the bound PROTAC. One of skill in the art having read and understood Buckley would realize that a PROTAC comprising an ERa binding ligand and an XIAP binding moiety would target ERa for selective degradation. One of ordinary skill in the art would reasonably deduce that selectively degradation of ERa in breast cancer cells would result in inhibition of the biological activity of ERa from the breast cancer cell. The PROTACs of Buckley allow for a skilled artisan to selectively target ERa for degradation while the ADC platform of Lee allows for said PROTACs to be directed to HER2 positive breast cancer cells through the use of an anti-HER2 antibody. One of ordinary skill in the art would have a reasonable expectation of success making such a combination because: 1) Ali teaches that inhibition of ERa is an effective means to fight breast cancer, 2) Bhakta provides an ADC platform that produces ADCs that are known to target HER2, are known to be effective in anti-breast cancer pharmaceutical formulations and possess a close to homogeneous and predictable structure as well as a means to attach a drug (or PROTAC), 3) Buckley teaches that a heterobifunctional PROTAC comprising an XIAP binding moiety and an ERa binding moiety would target ERa for selective degradation, 4) Chen teaches of a specific molecule known to bind XIAP, 5) Jain teaches that a linker comprising a PEG4 moiety would decrease the hydrophobicity of the molecule, which would attenuate issues related to aggregation and 6) the instant claimed PEG2 linker is sufficiently close to the PEG4 moiety of Jain to be considered an obvious variant, given that adding PEG moieties comprising various numbers of repeat units to different parts of an immunoconjugate is so routine in the art that, absent any data clearly showing criticality, that the difference between the two verges upon triviality.
Additionally, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934)(the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.).
Response to Arguments
Applicant's arguments filed 09/15/2025 have been fully considered but they are not persuasive.
Applicant’s arguments are again situated around the number of PEG repeat units connecting the PROTAC element. Applicant argues that the change from a PEG4 linker to a PEG3 or PEG2 linker is not merely a change in “ranges or amounts” but change in chemical structure. In response, numbers are often used to represent physical quantities and, in the instant case, when the number in question is varied, the structure of the molecule does change, but the number in question also refers to the relative amount of a structure having a specific chemical character, which is subject to optimization.
Applicant additionally argues that the reduction of the number of PEG repeat units is a change that teaches away from the Jain reference because reducing the number of PEG repeat units (e.g., from the 4 of Jain to the instant claimed 3 or 2) would decrease hydrophilicity. In response, the number of PEG repeat units is a numerical quantity subject to optimization. A single PEG unit between the ligase recruiting and targeting element of a PROTAC would likely add little hydrophilicity but 100 PEG units between the units could easily add unneeded bulk and situate the ligase recruiting element too far from the targeting element. Additionally, the fact that varying the length of PEG linkers within PROTAC elements is highly routine in the art is evidenced by the fact that commercially available PROTAC linkers comprising PEG chains of varying length before the effective filing date of the instant application. BroadPharm (BroadPharm; PEG Linkers & PEGylation Reagents Supplier; URL = https://broadpharm.com/product-categories/protac; First Available = 11/12/2015) teaches of numerous pre-made PROTAC linkers comprising an AHPC moiety (an E3 ligase recruitment unit) and a carboxy acid moiety (for attachment to a targeting ligand) separated by PEG chains comprising 2, 3, 4, 5, 8 and 12 repeat units (BroadPharm, p 3-4). As such, it is evident that, in certain applications, a shorter PEG chain within a PROTAC (e.g., the PEG2 moiety of BroadPharm) is desirable whereas in other applications a longer PEG chain within a PROTAC (e.g., the PEG12 moiety of BroadPharm) is desirable. The exact number is a matter of balance and routine optimization and routine optimization is within the purview of one of skill in the art.
Claim(s) 47, 51, 58-61 and 65-66 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bhakta (Bhakta, et al., WO 2016/040856 A2; Published 03/17/2016, of record) in view of Buckley (Buckley, et al., Angew Chem Int Ed Engl 2014 53(9):2312, of record), Raker (Raker, et al., Front. In Immuno. 2016 Vol. 7 Article 123, of record), Jain (Jain et al., Pharm. Res 2015 32:3526, of record) and Chen (Chen, et al., WO 2015/071393 A1; Published 03/21/2015, of record).
Bhakta teaches on the subject of cystine engineered antibody drug conjugates (Bhakta, Abstract). Bhakta teaches that antibodies with cystine substations can be conjugated via the engineered thiol groups to produce ADCs with a close to uniform stoichiometry of 2 drugs per antibody (same as DAR = 2) in a homogeneous and site-specific conjugation scheme (Bhakta, ¶ 0009). Bhakta teaches that the ADC of Bhakta can is present in a pharmaceutical formulation further comprising pharmaceutically acceptable excipients (Bhakta, ¶ 00445). Bhakta teaches that the conjugate of Bhakta binds cells that produce autoimmune antibodies associated with autoimmune disease (Bhakta, ¶ 0085) and that thyroiditis is a preferred target disease for the ADCs of Bhakta (Bhakta, ¶ 00455). Bhakta teaches that the conjugate of Bhakta comprises an anti-CD19 antibody (an antigen expressed on B cells) (Bhakta, ¶ 00139). Bhakta teaches that the conjugate structure of the ADC of Bhakta is maleimidocaproyl valine citrulline para-amino benzyl-MMAE (same as Ab-MC-vc-PAB-MMAE; which is the same as the conjugate structure of claim 47 except with MMAE as the drug instead of the PROTAC of claim 47 as the drug) (Bhakta, Claim 46).
Bhakta does not teach that that the drug moiety of the conjugate is a PROTAC having the structure E3LB-L2-PB, wherein E3LB is the tetrahydro-benzodiazepinone depicted in claim 47, L2 is a PEG2 moiety and PB is a adenylate cyclase (AC) binding ligand.
Buckley teaches that PROTACs are heterobifunctional molecules that contain a ligand for an E3 ligase, a linker and a ligand that is to be targeted for degradation (Buckley, p 9, ¶ 3). Buckley teaches that this molecule can bind to both the E3 ligase and the target, inducing the formation of a ternary complex and that this “hijacking” E3 ligase can then lead to the polyubiquitination of the target protein, followed by its degradation by the proteasome (Buckley, p 9, ¶ 3). Buckley also teaches that E3 ligase inhibitors targeting XIAP were some of the first E3 ligase inhibitors discovered (Buckley, p 14, ¶ 3). Buckley teaches that there is a strong desire to develop PROTACs using small molecule ligands (as opposed to peptidic ligands, which are less drug-like and less stable than small molecules) to target E3 ligases such as cIAP1 and MDM2 (Buckley, p 10, ¶ 3). Regarding the specific E3 ligase to be used, cIAP1 is a member of the IAP genus, of which XIAP1 is also a member. Moreover, both cIAP1 and XIAP1 are species within the E3 ligase genus. Buckley teaches that PROTACs have advantages over other interventions, such as inhibitors, namely: 1) PROTACs do not need to inhibit interactions that occur over large surface areas; instead methods such as PROTACs require only a ligand capable of binding to the target protein to induce degradation and 2) unlike antagonists and inhibitors, which only control specific activities of their targets, PROTACs lead to degradation of the target protein and, thus, of function of other activities (such as scaffolding) (Buckley, p 9, ¶ 1).
Raker teaches on the subject of therapeutic strategies targeting cyclic adenosine monophosphate (cAMP) effects for the treatment of autoimmune disorders (Raker, Abstract). Raker teaches cAMP is an essential signal in the induction of antibody production (Raker, p 4, ¶ 1). Raker teaches that the enzyme adenylate cyclase (AC) catalyzes cAMP formation from ATP (Raker, p 1, ¶ 1). Raker teaches that most inhibitors of anabolic or catabolic cAMP enzymes are noncovalent, that an issue associated with noncovalent inhibitors is the cells becoming resistant to their effects and that targeting these enzymes for degradation using PROTACs can overcome this resistance effect (Raker, p 7, ¶ 2).
Chen teaches on the subject of tetrahydro-benzodiazepinones (Chen, Abstract). Chen teaches that the tetrahydro-benzodiazepinones of Chen bind both XIAP and cIAP (Chen, p 1, ¶ 2). Chen teaches that the tetrahydro-benzodiazepinones of Chen are of Formula I’ (Chen, p 7, ¶ 2):
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Chen also teaches that the allowable variable groups for Formula I’ (R1, R2, R3, R4, R5, R9, W, X and Z) are the same as the corresponding variable groups for the XIAP binding moiety of claim 47 (Chen, p 7-p 9).
Jain teaches that hydrophobicity in linkers is problematic due to its propensity to cause aggregation, that PEG linkers can attenuate this effect and that ADCs comprising PEG4 linkers were markedly more effective than hydrocarbon linkers of the same length (Jain, p 3535, ¶ 2).
It would be prima facie obvious to one of ordinary skill in the art to combine the cystine engineered anti-CD19 ADC of Bhakta with the PROTAC technology taught by Buckley, the XIAP binding moiety taught by Chen and a PEG2 linker that is similar to the PEG4 linker taught by Jain. The net result of this combination would be the cystine engineered anti-CD19 ADC of Bhakta with the drug moiety replaced with a PROTAC comprising the XIAP binding moiety of Chen and an AC binding ligand, wherein the XIAP binding moiety and the binding ligand are linked by a PEG2 linker and to use the resultant PROTAC antibody conjugate in a method of treating thyroiditis. The motivation for making such a combination is to create an ADC that can be used to treat thyroiditis by selectively targeting ACfor degradation through the use of the bound PROTAC. One of skill in the art having read and understood Buckley would realize that a PROTAC comprising an AC binding ligand and an XIAP binding moiety would target AC for selective degradation. One of ordinary skill in the art, having read and understood Raker, would reasonably deduce that selectively degradation of AC in B cells would result in lower levels of cAMP in the B cells which, in turn, would lead to the B cells producing fewer thyroid-targeting autoantibodies. The PROTACs of Buckley allow for a skilled artisan to selectively target AC for degradation while the ADC platform of Bhakta allows for said PROTACs to be directed to B cells through the use of an anti-CD19 antibody. One of ordinary skill in the art would have a reasonable expectation of success making such a combination because: 1) Raker teaches that AC catalyzes cAMP formation and cAMP stimulates antibody production in B cells, 2) Bhakta provides an ADC platform that produces ADCs that are known to target CD19, are known to be effective in anti-thyroiditis pharmaceutical formulations and possess a close to homogeneous and predictable structure as well as a means to attach a drug (or PROTAC), 3) Buckley teaches that a heterobifunctional PROTAC comprising an XIAP binding moiety and an AC binding moiety would target AC for selective degradation and this would lead to lower cAMP levels in the targeted B cells which would result in lower levels of autoantibody production, 4) Chen teaches of a specific molecule known to bind XIAP, 5) Jain teaches that a linker comprising a PEG4 moiety would decrease the hydrophobicity of the molecule, which would attenuate issues related to aggregation and 6) the instant claimed PEG2 linker is sufficiently close to the PEG4 moiety of Jain to be considered an obvious variant, given that adding PEG moieties comprising various numbers of repeat units to different parts of an immunoconjugate is so routine in the art that, absent any data clearly showing criticality, that the difference between the two verges upon triviality.
Additionally, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934)(the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.).
Response to Arguments
Applicant provided no arguments specific to this rejection in the remarks entered 9/15/2025.
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 47 and 49-55 and 58-64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,666,581 B2 in view of Bhakta (Bhakta, et al., WO 2016/040856 A2; Published 03/17/2016, of record) and Chen (Chen, et al., WO 2015/071393 A1; Published 03/21/2015, of record).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the patented and instant claims are directed toward a structurally similar antibody-PROTAC conjugate as well as methods of treating human disease requiring the use of such antibody-PROTAC conjugates. Regarding instant claim 47, patented claims 1 and 17 are directed toward an antibody-PROTAC structure that reads on instant claim 47 with patented claim 17 providing the structure of the linker linking the antibody to the PROTAC and patented claim 1 providing the structure similar to the PROTAC itself. Regarding instant claims 49-50, patented claim 2 is directed toward a PB that binds ERa. Regarding instant claims 52-55, patented claims 3-4 are directed to a conjugate comprising an anti-HER2 antibody. Regarding instant claims 58-59, patented claim 1 is directed to a conjugate with a DAR ranging from 1 to 8. Regarding instant claim 60, patented claim 20 is directed toward pharmaceutical compositions comprising one or more pharmaceutically acceptable excipients and the aforementioned conjugate. Regarding claims 62-64, patented claims 21-22 are directed to a method of treating HER2 positive breast cancer, said method comprising administering the conjugate to a patient.
The ‘581 patent does not teach that the anti-HER2 antibody is a cystine-engineered antibody comprising the E3LB of claim 47.
Chen teaches on the subject of tetrahydro-benzodiazepinones (Chen, Abstract). Chen teaches that the tetrahydro-benzodiazepinones of Chen bind both XIAP and cIAP (Chen, p 1, ¶ 2). Chen teaches that the tetrahydro-benzodiazepinones of Chen are of Formula I’ (Chen, p 7, ¶ 2):
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Chen also teaches that the allowable variable groups for Formula I’ (R1, R2, R3, R4, R5, R9, W, X and Z) are the same as the corresponding variable groups for the XIAP binding moiety of claim 47 (Chen, p 7-p 9).
Bhakta teaches on the subject of cystine engineered antibody drug conjugates (Bhakta, Abstract). Bhakta teaches that antibodies with cystine substations can be conjugated via the engineered thiol groups to produce ADCs with a close to uniform stoichiometry of 2 drugs per antibody (same as DAR = 2) in a homogeneous and site-specific conjugation scheme (Bhakta, ¶ 0009).
It would be prima facie obvious to combine the anti-HER2 antibody PROTAC conjugate of the ‘581 patent with the tetrahydro-benzodiazepinone XIAP binding moiety of Chen and the cystine engineered antibody of Bhakta. Both the tetrahydro-benzodiazepinone of the ‘581 patent and the tetrahydro-benzodiazepinone of Chen share the characteristic of being an E3 ligand binding molecule and, as such, substitution of one for another would constitute a simple substation of one art element for another to yield predictable results, which is a prima facie obvious change under the KSR v Teleflex decision. Bhakta teaches that the use of cystine engineered antibodies allows for one to produce ADCs with close to uniform stoichiometry (with a DAR =2) and in a homogeneous and site-specific conjugation scheme, which would produce a product that is more consistent and has less lot-to-lot variation. One of ordinary skill in the art would have a reasonable expectation of success combining the anti-HER2 antibody PROTAC conjugate of the ‘581 patent with the tetrahydro-benzodiazepinone XIAP binding moiety of Chen and the cystine engineered antibody of Bhakta because: 1) the substation of the tetrahydro-benzodiazepinone of Chen instead of the tetrahydro-benzodiazepinone of the ‘581 patent is a simple substation based on the ability of both molecules to bind E3 ligase and 2) the engineered cystines of Bhakta produces a more uniform conjugate with known stoichiometry.
Regarding the limitation that the resultant DAR of the antibody-PROTAC conjugates be about 2, it is prima facie obvious to one of ordinary skill in the art to start with the DAR range taught by the ‘581 patent (1 to 8) and arrive at a DAR of about 2 via routine experimentation. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F. 2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) See MPEP 2144.05. Further with respect to optimal dosing regimens, it is not inventive to discover such regimens by routine experimentation when general conditions of a claim are disclosed in the prior art. See in re Aller, 220 F.2d 545, 456, 105 USPQ 233, 235 (CCPA 1955) and MPEP 2144.05(11).
Response to Arguments
Applicant provided no arguments specific to this rejection in the remarks entered 09/15/2025.
Claims 47 and 49-55 and 58-66 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,666,581 B2 in view of Bhakta (Bhakta, et al., WO 2016/040856 A2; Published 03/17/2016, of record) and Chen (Chen, et al., WO 2015/071393 A1; Published 03/21/2015, of record) as applied to claims 47-55 and 58-64 above and in further view of Raker (Raker, et al., Front. In Immuno. 2016 Vol. 7 Article 123, of record)
The combined teachings of the ‘581 patent, Bhakta and Chen are discussed above.
The combined teachings of the ‘581 patent, Bhakta and Chen discussed above do not teach that the PB of the PROTAC binds AC and that the antibody of the PROTAC-antibody conjugate binds CD19. The combined teachings of the ‘581 patent, Bhakta and Chen discussed above do not teach the administration of the AC-targeting PROTAC anti-CD19 PROTAC-antibody conjugate for the treatment of the autoimmune disease thyroiditis.
In addition to the teachings discussed above, Bhakta teaches that the conjugate of Bhakta binds cells that produce autoimmune antibodies associated with autoimmune disease (Bhakta, ¶ 0085) and that thyroiditis is a preferred target disease for the ADCs of Bhakta (Bhakta, ¶ 00455). Bhakta teaches that the conjugate of Bhakta comprises an anti-CD19 antibody (an antigen expressed on B cells) (Bhakta, ¶ 00139).
It would be prima facie obvious to one of ordinary skill in the art to start with the anti-HER2 PROTAC-antibody conjugate collectively taught by the ‘581 patent, Bhakta and Chen discussed above, substitute the ERa PB for an AC PB, substitute the anti-HER2 antibody for an anti-CD19 antibody and administer the resultant AC-targeting PROTAC-antibody conjugate for the treatment of thyroiditis. The net result of this combination would be the cystine engineered anti-CD19 PROTAC-antibody conjugate comprising a PROTAC comprising the XIAP binding moiety of Chen and a PB that binds AC. The motivation for making such a combination is to create an ADC that can be used to treat thyroiditis by selectively targeting AC for degradation through the use of the bound PROTAC. One of skill in the art, understanding the mechanism of action of the PROTAC of the ‘581 patent would realize that replacing the ERa PB with an AC PB would cause the PROTAC to foment the selective degradation of AC instead of ERa. One of ordinary skill in the art, having read and understood Raker, would reasonably deduce that selectively degradation of AC in B cells would result in lower levels of cAMP in the B cells which, in turn, would lead to the B cells producing fewer thyroid-targeting autoantibodies. One of ordinary skill in the art would have a reasonable expectation of success making these substitutions because: 1) Raker teaches that AC catalyzes cAMP formation and cAMP stimulates antibody production in B cells, 2) Bhakta provides an ADC platform that produces ADCs that are known to target CD19, are known to be effective in anti-thyroiditis pharmaceutical formulations and possess a close to homogeneous and predictable structure as well as a means to attach a drug (or PROTAC) and 3) one of skill in the art familiar with the function of the PROTAC of the ‘581 patent would realize that replacing the ERa PB with an AC PB would cause the PROTAC to degrade AC, which would lead to lower cAMP levels in B cells, which would lead to lower autoantibody production by these B cells.
Response to Arguments
Applicant provided no arguments specific to this rejection in the remarks entered 09/15/2025.
Conclusion
Claims 47 and 49-66 are rejected.
No claims are allowed
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643