DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statements filed on January 23, 2024, July 7, 2025, and January 15, 2026 are acknowledged and have been considered by the examiner.
Claim Objections
Claims 1, 13, 17, and 22 objected to because of the following informalities:
In claims 1 and 17, in the list of chelating agent groups which moiety C of the provided structure may be selected from (ii), the 11th and 12th structures from the list (the first and second structures labeled as DOTA-GA) are identical duplicates. One must be removed in each instance.
Additionally, in claims 1 and 17, among the listing of possible BS groups, “carbamate” and “phosphoramide” are each duplicated. One must be removed in each instance.
In claim 13, among the list of linking groups the “L” moiety is claimed to be capable of forming upon reacting are several duplicate groups. These duplications are “amide,” “ester,” “hydrazone,” methylene alkoxy carbamate,” “phosphoramide,” “thiazolidine,” and “thioester.” Additionally, “disulfide” and “disulphide” are alternative spellings of the same linking group. One must be removed in each instance of duplication. Furthermore, “carbamate” is listed three times. Two instances must be removed.
In claim 22, the stated list of cancers includes a list of acceptable names for cancer types, but recites “myeloma cells” as one of the members of the list. The recitation of “cells” is unnecessary and obfuscating, as the disease is just referred to as myeloma. The word “cells” should be removed in this instance.
Appropriate correction is required.
Claim Interpretation
Regarding claim 2, at the end of the claim, the applicant recites that “…when n>1 and a respective point of attachment is indicated on any one of Ra, Rb, and Rc, then it can be independently present in one or more of the peptide monomeric units, optionally in one peptide monomeric unit most distant from the other point of attachment indicated in the respective structure.” The examiner interprets the words following “optionally” to not be required structural elements of the claim and not limit the claim to only that embodiment.
Regarding claim 7, the applicant recites “…wherein M is a radioactive isotope optionally selected from…” The examiner interprets the words following “optionally” to not be required structural elements of the claim and not limit the claim. Thus, no specific radioactive isotopes are required by the language of claim 7.
Claim 8 provides several representations for possible (BS)xC structures. It is interpreted that the combinations of AA groups with or without additional BS groups represent the possible structures of the (BS)x region of the larger (BS)xC structure. In this way, the AA groups are considered to be different forms of BS groups.
Claim 8 states that “each x is 0, 1, or 2.” While “each” implies there are multiple instances of “x,” the examiner only notes the recitation of x in “wherein (BS)xC is…” in the second line of the claim. It is interpreted that this is the only “x” in the claim which may be 0, 1, or 2.
Regarding claim 12, the applicant claims a method for treatment of the human or animal body. The applicant also defines on page 41 of the instant specification that “treatments may be therapeutic and/or prophylactic.” MPEP §211.01 states “Where an explicit definition is provided by the applicant for a term, that definition will control interpretation of the term as it is used in the claim.” Thus, the beginning of claim 12 is interpreted to mean that the treatment may be therapeutic or prophylactic. However, the claim further states that this method of treatment is “by surgery or therapy,” which narrows the claimed “treatment” to just those that are therapeutic and excludes prophylactic treatments. Therefore, claim 12 is interpreted to exclude prophylactic treatment from its scope and just include therapeutic treatment and surgery and diagnostic methods.
Claim 13 states that moiety L may be “a moiety capable of forming, upon reacting” various linking groups. The examiner interprets the “capable of forming” language to be functional language. This language does not provide structural requirements for moiety L. Therefore, any moiety that possesses the claimed function, regardless of its structure, reads on the claim.
Claim 20 is drawn toward a method of use of the compound of claim 1. This method is claimed to be for the purpose of therapy or prophylaxis, guided surgery, diagnosis of a disease or disorder, or targeted delivery of a therapeutic or diagnostic agent. The recitation of “a method for…” describes functional language and this part of the claim does not provide any required steps in the claimed method. Claim 20 is interpreted to only contain required structural elements of the method in its last paragraph. If prior art reads on these structural requirements, even the art teaches a different use of the method, it will read on the claim.
Regarding claim 23, the applicant recites “…wherein the compound has a prolonged residence … optionally beyond 1 h or beyond 6 h post injection.” The examiner interprets the words following “optionally” to not be required structural elements of the claim and not limit the claim to only that embodiment. Thus, no specific minimum residence time values are required by the claim, only that it is “prolonged.”
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 8-9, 13, and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The disclosure does not provide a representative number of examples of the compounds with varying structures. Regarding claims 1-2 and 8-9, only structures 1-8, 19, 20, 28, and 29 contain all the limitations of the core bivalent FAP ligand and a chelating group. Only three chelating groups are provided and only two distinct BS regions are provided. Insufficient written description is provided for the majority of the claimed chelating groups and BS structures. While the list of possible groups is disclosed in the specification the representative species provided are limited in number and chemical diversity.
Regarding claims 13 and 17, as these claims do not require a chelating group be present, there are more disclosed structures that read on these claims containing more coverage of the claimed scope of BS structure and therapeutic and diagnostic agents. However, the disclosure is still not commensurate with the scope of the claims. For example, structures P16 and P17 are the only provided examples for claim 13. These examples cover a very limited amount of the breadth of scope claimed regarding the possible structures of moiety L. None of the possible moiety L structures provided on the top of page 46 of the specification are taught as example structures.
Although the disclosure provides embodiments that read on some aspects of the claims, it does not expressly teach the other structures in a way that provides sufficient support for everything claimed. Thus, claims 1-2, 8-9, 13, and 17 are rejected for failing to comply with the written description requirement of §112(a).
Claims 12 and 19-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The disclosure does not provide a representative number of examples of the compounds with varying structures being used for the claimed methods. Working examples are provided for the administration and use of Bi-ESV6-DOTAGA (structure 1) with chelated 177Lu (structure 5), 175Lu (structure 5a), and 69Ga (structure 6a) in mice with implanted xenograft tumors for biodistribution and therapeutic studies. These examples only teach the use of a single (BS)x region and single C moiety. Insufficient written description is provided for the majority of the claimed chelating groups and BS structures. While additional structures are described, their use in the claimed methods is not, meaning that the disclosure is not commensurate with the scope of the claims.
Although the disclosure provides embodiments that read on some aspects of the claims, it does not expressly teach the use of other structures in a way that provides sufficient support for everything claimed. Thus, claims 12 and 19-23 are rejected for failing to comply with the written description requirement of §112(a).
Claims 20-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for therapy of, guided surgery on, and targeted delivery to a subject suffering from a disease or disorder and diagnosis of a disease or disorder via nuclear imaging, wherein FAP is a marker of the disease or disorder or is enriched at the site of the disease or disorder, such as certain cancers, inflammation, atherosclerosis, fibrosis, tissue remodeling, or keloid disorder, does not reasonably provide enablement for prophylaxis of, guided surgery on, or targeted delivery to a subject having risk for a disease or disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. These factors include, but are not limited to:
The breadth of the claims;
The nature of the invention;
The state of the prior art;
The level of one of ordinary skill;
The level of predictability in the art;
The amount of direction provided by the inventor;
The existence of working examples; and
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427, F.2d 833, 839, 166 USPQ 18, 24 (1970). To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, state and predictability of the art, and relative skill level
The invention of claims 20-23 relates to methods of treatment, guided surgery, diagnosis, and targeted delivery performed on a subject for the purpose of therapy, prophylaxis, or diagnosis of a disease or disorder. This method comprises administering a therapeutically or diagnostically effective amount of amount of the compound of claim 1 or a pharmaceutical composition comprising the compound and an acceptable excipient.
The relative skill of those in the art who would practice this method is high, likely that of a one who has obtained a PhD or MD.
In the art, it is known that FAP is a biomarker connected to several diseases and disorders, including several cancers, as it can be a marker of activated fibroblast cells and cancer-associated fibroblasts. It is also known that FAP is endogenously expressed in some healthy cells and that activated fibroblasts can engage in healthy tissue homeostasis.
Successful disease prevention (prophylaxis) is much less predictable than therapeutic treatment of an already established disease or disorder. Enrichment of a biomarker like FAP at a site of disease tends to mean that molecules that selectively bind to the biomarker will become enriched at that site upon administration. Thus, therapy, surgery, and targeted delivery for the claimed diseases and disorders of claims 21 and 22 seem enabled, as FAP may play a role in each of these pathophysiologies. However, it is not clear that FAP is an effective preemptive susceptibility/risk biomarker (enriching at site of disease prior to the establishment of the disease state) for the claimed diseases and disorders. Even if it was, it is not predictable whether early FAP targeting would prevent the establishment of the claimed diseases.
The breadth of the claims
The claims are broad insofar as the method encompasses therapy, prophylaxis, guided surgery, diagnostic imaging, and targeted delivery. These medical interventions are very different and are often performed by different specialized practitioners. Additionally, the claim encompasses administration to subjects both suffering from a disease or disorder and having risk for a disease or disorder. Furthermore, the claimed diseases and disorders differ in pathophysiology.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides little direction or guidance for practicing the claimed invention in its “full scope.” Working examples are provided for administration of Bi-ESV6-DOTAGA with a chelated metal to mice with implanted xenograft tumors (wt and hFAP positive HT-1080 cells) for biodistribution and therapeutic studies. These examples teach the administration of the compound to mice and enrichment of the compound at a genetically modified xenograft tumor. The examples also teach the therapeutic treatment of hFAP positive xenograft tumors in mice. No direction or guidance is provided for guided surgery or disease prevention. No evidence of efficacy of other compounds for these latter purposes is provided.
The quantity of experimentation necessary
Experimentation to determine a therapeutically or diagnostically effective amount of material to administer to a subject can be significant. Furthermore, determining if any given compound is effective for the prevention of a disease is more significant and often spans longer periods of time. The claimed diseases are not derived from bacterial or viral infections, so challenge studies are not reasonably feasible. Rigorous prevention studies would require large cohorts and a long time horizon of observations to monitor disease occurrence in treatment and comparison groups. Further experimentation to provide evidence that the intervention is the primary cause of any observed disease prevention would additionally be complex.
Because of the known unpredictability of the art, and in the absence of experimental evidence and working examples, it is difficult to determine the amount of experimentation required to determine an effective way to use the compound of claim 1 for the prophylaxis of, guided surgery on, or targeted delivery to a subject at risk for a disease or disorder who does not already have an established FAP-positive disease or disorder.
Accordingly, the instant claims do not comply with the enablement requirement of §112(a), since to practice the claimed invention in its “full scope,” a person of ordinary skill in the art would have to engage in an unreasonable amount of experimentation, with no reasonable expectation of success.
Claims 12 and 19-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of using compounds of structures 5, 5a, and 6a (or those that are very structurally similar) for therapy, diagnosis, surgery, and targeted delivery, does not reasonably provide enablement for methods of using all other structures encompassed by these claims for these uses. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the invention commensurate in scope with these claims.
As described above, determination of compliance with the enablement requirement of 35 U.S.C. 112(a) is done using the framework of the aforementioned Wands factors.
The nature of the invention, state and predictability of the art, and relative skill level
The invention of claims 12 and 19-23 relates to methods of using compounds of claim 1 for therapy, surgery, diagnosis, and targeted delivery. This method comprises administering a therapeutically or diagnostically effective amount of amount of the compound of claim 1 or a pharmaceutical composition comprising the compound and an acceptable excipient.
The relative skill of those in the art who would practice this method is high, likely that of a one who has obtained a PhD or MD.
In the art, it is known that FAP is a biomarker connected to several diseases and disorders, including several cancers, as it can be a marker of activated fibroblast cells and cancer-associated fibroblasts. It is also known that FAP is endogenously expressed in some healthy cells and that activated fibroblasts can engage in healthy tissue homeostasis. Furthermore, it is known that skilled chemists are able to generate a variety of molecules.
Efficacy of a compound for these claimed methods in vivo can be difficult to predict. While the core bivalent FAP ligand can be confidently predicted to enable binding of a compound to the FAP protein if the two molecules come into contact with the correct orientation, the BS and C regions of the compound of claim 1 are more variable and thus impart unpredictability regarding efficacy for these methods of use. For example, the structures of section (i) describing some of the possible options for the structure of moiety C (pg. 4 of instant claim set) include a wide variety of structures that will possess different strengths of metal chelation. It would be difficult to predict these binding affinities. A weak binding chelating group would prevent efficacy for these claimed uses, as these uses rely on the presence of a metal bound to the chelating group staying bound while the compound is in the body of a subject. Furthermore, the range of BS region structures could impart a range of properties on the compound, some of which could impact the stability of the molecule (and thus its efficacy). For example, the claimed BS structures include esters, which are known to be readily hydrolyzed in the body. Such hydrolysis would disconnect the chelated metal from the FAP targeting group, rendering the compound ineffective. It would be difficult to predict the effect of each of the claimed possible BS structures on the pharmacokinetic and pharmacodynamic properties of the compound.
The breadth of the claims
The claims are broad insofar as the method of use claims depend on claim 1 and thus encompass methods of using any of the structures within the scope of claim 1, which itself is broad. The broad range of possible BS structures includes groups possessing different structures, heteroatoms, reactivities, and stabilities, all of which can impact the efficacy of a compound. Additionally, the range of structures which can be represented by moiety C is also broad and encompasses structures that will have different metal chelating affinities and pharmacological properties.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides little direction or guidance for practicing the claimed invention in its “full scope.” Working examples are provided for the administration and use of Bi-ESV6-DOTAGA with chelated 177Lu (structure 5), 175Lu (structure 5a), and 69Ga (structure 6a) in mice with implanted xenograft tumors for biodistribution and therapeutic studies. These examples only teach the use of a single (BS)x region and single C moiety. No direction is provided as to the process for determining a therapeutically or diagnostically effective amount of the compounds. No evidence of efficacy of other compounds for any of these claimed uses is provided.
The quantity of experimentation necessary
Experimentation to determine a therapeutically or diagnostically effective amount of a compound to administer to a subject can be significant. Furthermore, the breadth of the scope of claim 1 encompasses a vast set of possible compounds. Determination of the pharmacological properties of each of these molecules would require separate syntheses, several preliminary in vitro experiments, and several in vivo experiments. While a skilled chemist might be able to make any of the claimed compounds, synthesis and purification of the full breadth of structures would be significant work given the range of properties of the possible structures. Additional biological assessments would be further complex and significant in quantity.
Because of the known unpredictability of the art, and in the absence of experimental evidence and working examples, it is difficult to determine the amount of experimentation required to determine what compounds within the scope of claim 1 are capable of effectively being used for therapy, surgery, diagnosis, and targeted delivery in a subject.
Accordingly, the instant claims do not comply with the enablement requirement of §112(a), since to practice the claimed invention in its “full scope,” a person of ordinary skill in the art would have to engage in an unreasonable amount of experimentation, with no reasonable expectation of success.
Claim Rejections - 35 USC § 112(b)
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.
Claims 2, 8, 9, 12, 13, 15-17, and 19-23 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.
Claim 2 recites the limitation of “Rc” in the third to last line. There is insufficient antecedent basis for this limitation in the claim as no Rc is provided in any of the structures. Therefore, the claim is indefinite. The claim will be examined interpreting the larger phrase to refer to just Ra and Rb.
Claim 2 recites the limitation "the peptide monomeric units" in the second to last line. There is insufficient antecedent basis for this limitation in the claim. Therefore, the claim is indefinite. The claim will be examined interpreting this phrase to refer to the components of the aforementioned proteinogenic or non-proteinogenic amino acids.
Claim 2 recites that “each of Ra and Rb is independently selected from a side-chain residue of a proteinogenic or non-proteinogenic amino acid” but it is unclear what structures are specifically included or not included in this category. Amino acids are defined by the carboxylic acid and amino groups in a backbone portion of the structure. A non-proteinogenic amino acid may have any side chain. Therefore, the limitation of “a side chain … of a … non-proteinogenic amino acid” does not provide clear structural limitations for what each of Ra and Rb may be. Thus, the claim is indefinite.
The last paragraph of claim 2 describes the orientation of each BS linker group related to the points of attachment. Based on the limitations of claim 1 and 2, these attachment points may be to various atoms, and specific limitations are drawn to carbon, nitrogen, or oxygen atoms. For example, the * attachment point of the BS group closest to the core bivalent FAP ligand must to attach to the carbonyl carbon of the core bivalent ligand, the · attachment point of the BS group closest to C may attach to the carbon and nitrogen attachment points provided in sections (i) and (ii) of claim 1, and both attachment points may connect to carbon, nitrogen, and oxygen atoms at attachment points of other BS groups provided in claim 2. Claim 2 recites that for the BS groups, “when n>1 and a respective point of attachment is on any of Ra, Rb, and Rc, then it can be independently present in one or more of the peptide monomeric units.” Earlier in claim 2, the applicant states that n may be 0, 1, 2, 3, or 4. However, claim 2 is indefinite because it is not clear how to address the metes and bounds of the described limitation when it includes structures that could not possibly be generated. If the second to last provided BS group structure in the list of claim 2 is chosen and n is 4 and the attachment point is on all 4 peptide monomeric units (as is allowed by the claim – it is on one or more), then if this BS group was in any of the aforementioned situations in which it must connect to an already partially occupied oxygen, nitrogen, or carbon, these four attachment points would result in these atoms being in pentavalent, hexavalent, or heptavalent states, which is not possible. Considering the possible attachment points, there are scenarios in which the number of attachment points on peptide monomeric units being 2 or 3 would also result in combinations not possible to make. Therefore, claim 2 is indefinite for omitting necessary structural requirements to enable the proper linking of the provided BS groups to their attachment partners.
Claim 8 includes several possible AA groups in the provided structures. However, the structures of what AA might be is undefined. Furthermore, it is not understood what the subscript values of the AA groups represent. Thus, the claim is indefinite.
Claim 8 provides several representations for possible (BS)xC structures and states that x may be 0, 1, or 2. The AA groups are understood to represent possible structures of the BS groups selected (see Claim Interpretation). All of these structures require at least three AA groups to be present, therefore implying the presence of at least 1 BS group depending on what AA is (see paragraph above and Claim Interpretation). If x was 0, then there would be no BS groups, and thus no AA groups, which is incompatible with the provided structures. Therefore, the claim is indefinite.
Claim 9 recites that “each of AA1, AA2, and AA3 represents a proteinogenic or non-proteinogenic amino acid” but it is unclear what structures are specifically included or not included in this category. Amino acids are defined by the carboxylic acid and amino groups in the backbone portion of the structure. A non-proteinogenic amino acid may have any side chain. Therefore, the limitation of “non-proteinogenic amino acid” does not provide clear structural limitations for what each AA group may be. Thus, the claim is indefinite.
Claim 12 recites the limitation "the human or animal body" in line 3. There is insufficient antecedent basis for this limitation in the claim. Furthermore, claim 19 is rejected for its dependence on claim 12.
Claim 13 states that “L” could be “a moiety capable of forming, upon reacting” a long list of linking groups. The structures of molecules and portions of molecules are defined by the atoms and bonds contained within and not by what they are capable of forming after reactions are performed. It is unclear what range of reactions are encompassed by the claim and how many reaction steps are permitted. A skilled chemist can turn a vast set of arrangements of atoms into the listed linking groups given any reagents and equipment desired. However, the bounds of what the applicant considers to be capable of being turned into these linking groups is unclear. Therefore, this limitation does not provide clear structural limitations for what the moiety L could be. Thus, the claim is indefinite. Furthermore, claims 15-17 are rejected due to dependence on claim 13. While claim 14 also depends on claim 13, the structural requirements of claim 14 render the indefinite portion of the claim 13 limitations definite and claim 14 is not rejected.
Claim 19 recites the limitation "the conjugate" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 20 recites the limitation "the human or animal body" in part (c) of the claim. There is insufficient antecedent basis for this limitation in the claim. Furthermore, claims 21-23 are rejected due to dependence on claim 20.
Regarding claim 20, the phrase "such as" in part (c) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Furthermore, claims 21-23 are also rejected due to dependence on claim 20.
Claim 23 recites the limitation "the disease site" in line 2. There is insufficient antecedent basis for this limitation in the claim.
The term “prolonged” in claim 23 is a relative term which renders the claim indefinite. The term “prolonged” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, the time of residence of the compound at the disease site required in the claimed method is unclear.
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, 5, 7-10, and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 45-47 of copending Application No. 17/799,611 in view of Hayashida (Hayashida, O.; Nakashima, T., Bull. Chem. Soc. Jpn., 2012).
The claims of copending application 17/799,611 are drawn toward FAP-targeting compounds in which one or two FAP ligands are linked to a therapeutic or diagnostic agent. Various monovalent FAP-targeting species are provided. All bivalent species link two identical groups of a FAP ligand, a 4,8-functionalized quinoline ring, and a succinyl region. In most of these structures (structures 47-51 of conflicting claim 45), one FAP ligand is linked to an asparagine region (Figure 1, Blue) through a linkage between the succinyl region and the asparagine backbone and the other FAP ligand is linked to a triazole-modified lysine side chain (Figure 1, Red) and the two ligands are attached to each other through linkage between the asparagine side chain and the backbone of the modified lysine. In one other structure of conflicting claim 45 (structure 57), one FAP ligand is linked to a triazole-modified lysine side chain (Red) and the other ligand is linked to the same lysine via a connection between the
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succinyl region and the lysine backbone (Figure 1).
The copending application does not teach a bivalent compound linking the identical FAP-targeting groups through just a lysine and lacking a triazole ring.
Hayashida teaches multivalent cyclophane molecules linked through succinyl groups connected by a lysine in the same manner as the instant application (pg. 716, Fig. 1). Hayashida also teaches that bivalent ligand-receptor interactions are stronger than monovalent binding interactions (pg. 720, Fig. 5).
A person of ordinary skill in the art would have recognized that the linking method of Hayashida is a simple substitution for the linking chemistry of the reference application and that the lysine linkage of Hayashida serves the same function of the bivalent linkage of the reference application, enabling the linkage of two FAP-targeting groups and providing a carboxylate group from the lysine backbone for further modification of the compound. It would further be recognized that Hayashida also teaches converting monovalent species to bivalent species through the lysine linking group. Applying this method to the monovalent FAP-targeting molecules of the copending application would result in bivalent ligands with stronger target binding interactions.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Hayashida with the reference application. This would yield compounds that read on the instant claims.
Regarding instant claim 1, the conflicting claim 45 of the reference application teaches linking together two of the same FAP ligands as the instant application and attaching them to a chelator (structures 47-51 and 57). The reference application structures also have several examples that read on the (BS)X region of claim 1 of the instant application, such as that of structure 57. The reference application does not teach linking the FAP ligand regions through just a lysine group. Hayashida teaches linking identical groups together though the lysine backbone and side chain amines (pg. 716, Fig. 1).
Regarding instant claim 2, the bivalent compounds of conflicting claim 45 of the copending application have structures in the corresponding (BS)X regions that read on instant claim 2, such as that of structure 57.
Regarding instant claim 5, structure 12 from conflicting claim 45 of the copending application provides a monovalent FAP-targeting compound linked to a DOTAGA chelating group bound to 68Ga. Applying the lysine linking method of Hayashida to generate a bivalent FAP ligand would result in a compound that reads on instant claim 5.
Regarding instant claim 7, structure 12 from conflicting claim 45 of the copending application provides a monovalent FAP-targeting compound linked to DOTAGA modified with the same linker as instant claim 7 and chelating 68Ga. Applying the lysine linking method of Hayashida to generate a bivalent FAP ligand would result in a compound that reads on instant claim 7.
Regarding instant claim 8, the compounds of conflicting claim 45 of the copending application include structures in which the (BS)XC region reads on the instantly claimed options. For example, structure 57 reads on instant claim 8 when x is 0 (see claim interpretation and 112(b) rejection above).
Regarding instant claim 9, the compounds of conflicting claim 45 of the copending application include structures in which the (BS)XC region reads on the instantly claimed options. For example, structure 27 reads on the instantly claimed structure when each AA is absent.
Regarding instant claim 10, the compounds of conflicting claim 45 of the copending application include structures in which, if the linker of the copending application structure were switched with the lysine linker taught by Hayashida, would read on the instantly claimed options.
Regarding instant claim 13, the compounds of conflicting claim 45 of the copending application include structures in which, if the linker of the copending application structure were switched with the lysine linker taught by Hayashida, the structures would read on the instantly claimed structure, as many of the structures of the reference application comprise moieties capable of forming linking groups after reacting.
This is a provisional nonstatutory double patenting rejection. However, the reference application is in the ALLOWED status.
Claims 1, 2, 5, 7-10, and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of copending Application No. 18/698,132 in view of Hayashida (Hayashida, O.; Nakashima, T., Bull. Chem. Soc. Jpn., 2012).
Claims 1-14 of copending application 18/698,132 are drawn toward FAP-targeting compounds in which a FAP ligand is linked to a therapeutic or diagnostic agent and the linker region contains a carbocyclic or heterocyclic group.
The copending application does not teach a bivalent compound linking two identical FAP-targeting groups through a lysine to a therapeutic or diagnostic group.
Hayashida teaches multivalent cyclophane molecules linked through succinyl groups connected by a lysine in the same manner as the instant application (pg. 716, Fig. 1). Hayashida also teaches that bivalent ligand-receptor interactions are stronger than monovalent binding interactions (pg. 720, Fig. 5).
A person of ordinary skill in the art would have recognized that the multivalent molecules of Hayashida are comparable to the compounds of the reference application, as both are drawn to compounds used for their ability to participate in a binding interaction (cyclophanes to dyes and FAP ligands to FAP protein). One would have also recognized that the creation of a multivalent FAP binder would similarly improve its binding affinity to the FAP protein and that the lysine linker region is an effective means to this end.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate the teachings of Hayashida with the reference application. This would yield bivalent FAP targeting compounds that read on the instant claims.
Regarding instant claim 1, conflicting claim 1 of the reference application teaches FAP ligands that read on the FAP ligand region of the instantly claimed structure. Claim 1 of the reference application also teaches linking the FAP ligand to a diagnostic agent, which includes radiometal chelating groups. Hayashida teaches using a lysine linker to connect two of the same moieties (pg. 716, Fig. 1). Applying the lysine linker as a substitute for the B region of the reference application produces structures that read on claim 1 of the instant application.
Regarding instant claim 2, if the B2 carbocyclic or heterocyclic group of the copending application is substituted with the lysine taught by Hayashida (which would provide the benefit of a stronger protein binding interaction), the reference claims would read on instant claim 2.
Regarding instant claim 5, conflicting claim 12 of the reference application teaches incorporating a radioisotope in the chelator region of the structure.
Regarding instant claim 7, conflicting claim 12 of the reference application teaches regions that read on the claimed C structures.
Regarding instant claim 8, the reference application claims are drawn to structures that read on the claimed (BS)XC region when x is 0 (see claim interpretation and 112(b) rejection above).
Regarding instant claim 9, the reference application claims are drawn to structures that, if the cyclic linker was replaced with the lysine linker of Hayashida, would read on the claimed (BS)XC region when each AA is absent.
Regarding instant claim 10, the compounds of conflicting claim 14 of the copending application include structures in which, if the linker of the copending application structure were modified with the lysine linker taught by Hayashida and a bivalent ligand were made, the structures would read on the instantly claimed structure.
Regarding instant claim 13, the compounds of conflicting claim 14 of the copending application include structures in which, if the linker of the copending application structure were modified with the lysine linker taught by Hayashida and a bivalent ligand were made, the structures would read on the instantly claimed structure, as many of the structures of the reference application comprise moieties capable of forming linking groups after reacting.
This is a provisional nonstatutory double patenting rejection.
Allowable Subject Matter
Claims 11 and 14-16 would be allowable if rewritten to overcome the current objections and/or rejections of these claims. Claims 11 and 14 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Claims 15 and 16 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Conclusion
No claim is allowed.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612