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 .
Claim Status
Claims 40-62 are pending.
Priority
This application is filed 1/25/2024 and claims the benefit of domestic priority as below:
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Information Disclosure Statements
Three IDS(s) received on 4/24/2024, 4/23/2026 and 8/05/2026 have been considered unless marked with a strikethrough. The references which lack an English translation (e.g., English abstract only) have been marked with a strikethrough because their contents could not be adequately reviewed.
Claim Objections
Claim(s) 40, 42, 44, 48-51, 53 and 55-58 is/are objected to because of the following informalities:
Claims 40 and 48 are objected to because the sentences of definitions lack a punctuation (i.e., a comma, and a hyphen) and consistency. For example, the phrase “or polypeptide moiety, an oligo or polyethylene glycol or an oligo or polyvinylalcohol” should be “or poly- peptide moiety, an oligo- or poly- ethylene glycol, an oligo- or poly- vinylalcohol, or”. Other definitions also have the same issue.
Claims 40 and 48 are objected to because "R2 and R3 are the same or different active pharmaceutical ingredient moiety" should be “…moieties”.
Claims 42-44, 49-51, 55 and 57 are objected to because the term “optionally” is used in reciting the specific subset of anticancer agents. For clarity and proper claim format, the specific subset of anticancer agents should be recited in a separate dependent claim from the broader recitation, or otherwise presented more clearly.
Claims 46, 53 and 55 are objected to because the peptide notation method is inconsistent. Some are written using single letter amino acid notation (e.g., CGKRK), while others are written using three letter amino acid notation (e.g., -Ala-Ala-).
Claim 58 is 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.
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.
The rejections under this section are made when the scope of the claimed subject matter is not clear. (See MPEP 2173)
Claims 40-46, 48-57, and 59-62 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 claims 40, 42-44, 48-51, 55 and 57, the term "moiety" renders the claim indefinite
because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. In particular, the structural boundary and identify of each claimed moiety are unclear. Although, the specification provides a functional definition of a “reactive moiety” (paragraph [0019]), the structural boundary of the reactive moiety within the claimed compound remains unclear. A moiety generally refers to an identifiable portion or functional part of a larger molecule, the claims do not clearly identify which portion of the molecule constitutes each moiety or how each moiety is bounded to the remainder of the claimed compound or conjugates. Thus, it is unclear which chemical structures fall within the scope of the claimed moieties.
Claims 41, 45, 46, 52-54, 56 and 59-62 depend directly or indirectly from claims 40 or 48. These
dependent claims incorporate the same indefinite moiety limitations for the same reasons.
Regarding claims 40 and 48, the phrase "R2 and R3 are the same or different active
pharmaceutical ingredient moiety" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. In particular, it is unclear whether the scope of an “active pharmaceutical ingredient moiety” refers to an intact active pharmaceutical ingredient or to a residue derived therefrom upon incorporation into the compound of Formula (I).
In addition, the terms “oligo-“ and “poly-“ render the claim indefinite because the claim does
Not define the structural characteristics or boundaries of the recited “oligo-“ and “poly-“ moieties. The specification does not provide a definition or structural criteria for determining the scope of “oligo-“ and “poly-“. For example, with respect to an oligo- or poly-carboxylic acid moiety, it is unclear whether heterocyclic or other intervening groups may form part of the oligomeric or polymeric structure, or whether the structure is limited to an alkyl based backbone bearing carboxylic acid groups. The claim also does not identify what constitutes a repeating unit or otherwise provide structural criteria for determining the scope of the recited oligo- and poly-moieties. Accordingly, the recitation is susceptible to multiple reasonable structural interpretations, and it is unclear which chemical structures fall within the scope of R4.
Claims 41-46 and 61-62 depend directly from claim 40, and claims 49-55 depend directly from
claim 48. These dependent claims incorporate the same indefinite Formula (I) definitions for the same reason.
Regarding claims 48 and 60, the definition "n is a number between 0.01-10" renders the claim
indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. Formula (I(a)) depicts the “NH-X1-X2-(R5)n”, and R5 is defines as an antibody or antigen moiety. Thus, n appears to represent the number of R5 moieties present in the claimed conjugate. However, claims 48 and 60 permit n to have fractional values (e.g., 0.01 or 0.1). Accordingly, it is unclear because an individual conjugate molecule cannot structurally contain fractional values of an antibody or antigen moiety.
Claims 49-57 and 59-60 depend directly from claim 48. These dependent claims incorporate the same indefinite Formula (I) definitions as the same reason.
Claim 55 recites the limitation "CGKRK" in the body of claim. There is insufficient antecedent
basis for this limitation in the claim. Claim 48 defines R5 as an antibody or antigen moiety, whereases the specification describes CGKRK as a peptide that is a model antibody or a moiety/ fragment that “simulates” an antibody (paragraph [0031]). However, simulating the function of an antibody does not establish that CGKRK is itself an antibody or an antibody moiety, and the specification does not establish that CGKRK is an antigen or antigen moiety. Accordingly, CGKRK does not fall within the scope of R5 as defined in Claim 48.
Claim Rejections - 35 USC § 112, Enablement
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 40-57 and 59-62 are rejected under 35 U.S.C. 112, first paragraph, because the specification does not enable a person of ordinary skill in the art to make and use the invention throughout the full scope of the claims without undue experimentation. Although the specification enables certain Formula (I) compounds and selected trastuzumab/exatecan and trastuzumab/belotecan conjugates, the disclosure is not commensurate with the broader claimed genera and therapeutic uses. (see MPEP 2164.01, 2164.04, 2164.06, and 2164.08 )
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. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
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). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, and state and predictability of the art
The claims encompass dual payload Formula (I) compounds, antibody or antigen containing conjugates, method of treating cancer using Formula (I) compounds, and kits thereof. Although, the relevant researches recognize substantial skill in medicinal chemistry, bioconjugation, and antibody−drug conjugates (ADC) development, the performance of the claimed compounds and conjugates depends on interacting chemical and biological variables.
For Formula (I) compounds, material variables include payload identity and attachment position, compatibility of the two payloads with the remaining structural components, stability, solubility, cleavage or activation, retention of biological activity, biodistribution, and toxicity. In addition, the claimed conjugates depend on target expression, antibody specificity, internalization, linker stability, payload permeability, conjugation chemistry, product heterogeneity, drug-to-antibody ratio (DAR), payload release, clearance, and tumor penetration.
A person of ordinary skill does not establish enablement where the specification absents information needed to predict whether materially different embodiments will operate. (see MPEP 3164.03 and 2164.05)
Staudacher et al. ( Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required?, Br. J. Cancer, 117(12), 1736-1742, pub’d 10/24/2017) discloses that ADC activity and bystander killing depend on internalization, linker cleavage, the location of payload release, payload permeability (abstract, and bystander killing section). Staudacher further explains that cleavable and non-cleavable ADCs may operate through materially different mechanisms and that linker and payload characteristic may alter stability, the released drug species, and antitumor activity (bystander killing and conclusion section).
The specification provides no general method for determining which mechanism will govern a claimed antibody, antigen, targeting moiety, linker, payload, and tumor combination. It does not teach how to determine, across the full scope of the claims, whether efficient internalization is required, where cleavage and payload release will occur, or whether the released payload will produce a therapeutically useful bystander effect.
Donaghy (Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates, MAbs., 8(4), 659-71, pub’d 04/05/2016) discloses that ADC toxicity may arise from the antibody, target antigen, linker, payload, conjugation design, or premature payload release (abstract and introduction). Therefore, the complete conjugate may exhibit pharmacokinetic, biodistribution, stability, and toxicity properties that cannot be reliably predicted from the individual antibody, payload, or other components.
The specification fails to provide a predictive framework or representative pharmacokinetic, biodistribution, stability, and toxicity data sufficient to determine which of the broad claimed combinations would possess acceptable therapeutics without undue experimentation.
Sun et al. (Effects of Drug-Antibody Ratio on Pharmacokinetics, Biodistribution, Efficacy, and Tolerability of Antibody-Maytansinoid Conjugates, Bioconjug. Chem., 28(5), 1371-1381, pub’d 04/13/2017) shows that increasing DAR may increase in vitro potency while also causing faster clearance, increased liver accumulation, and a reduced therapeutic index (abstract, Fig 1, and results and discussion section). These results demonstrates that DAR is not a predictably monotonic and may require optimization for the particular antibody, target antigen, linker, and payload system (results and discussion section).
The specification exemplifies DAR4 conjugates but provides no comparative data or general method for identifying acceptable conjugates throughout the DAR range of 0.5 to 200 recited in claim 59. In particular, the specification does not explain how to prepare and use conjugates approaching the upper end of that range while maintaining acceptable stability, solubility, target binding, pharmacokinetics, biodistribution, efficacy, and tolerability.
Therefore, Staudacher, Donaghy and Sun support that changes in payload, linker, targeting moiety, target biology, conjugation design, and DAR may materially and interdependently affect efficacy, pharmacokinetics, biodistribution, and safety. Because those effects cannot reliably be extrapolated from the limited disclosed embodiments with insufficient guidance across the full claimed scope in the specification, a person of ordinary skill in the art would be require to engage in undue experimentation.
The breadth of the claims
A broad genus does not require an example of every species, but the disclosure must provide
representative examples or a scope of general applicability sufficient to practice the claimed scope without undue experimentation. (see MPEP 2164.01 and 2164.08)
For Formula (I) compounds, material variables include payload identity and attachment position, compatibility of the two payloads with the remaining structural components, stability, solubility, cleavage or activation, retention of biological activity, biodistribution, and toxicity. In addition, the claimed conjugates depend on target expression, the identify and binding of the antibody, antigen or other targeting moiety, internalization, linker stability, payload permeability, conjugation chemistry, product heterogeneity, DAR, payload release, clearance, and tumor penetration. Specifically, Claim 40 is not limited to the identified anticancer or immune modulating agents. The dependent claims identify exatecan, belotecan, camptothecin, auristatin, Monomethyl auristatin E (MMAE) or a doxorubicin moiety at R2 position as optional species, but the underlying genus remains broader. The claims also permit different reactive moieties, hydrophilic moieties, peptide sequences, and polymeric components. The conjugate claims add broad antibody or antigen moieties, multiple linker alternatives, n values between 0.01 and 10, and in claim 59, DAR values between 0.5 and 200.
The specification’s examples focuses on exatecan and belotecan, which are related topoisomerase I inhibitor payloads, and selected trastuzumab conjugates. It does not provide representative examples involving materially different payload classes, mixed payload combinations, immune modulating agents, or the broader antibody and antigen genus. Furthermore, the specification does not provide generally applicable criteria for determining which active agents have suitable attachment sites, which modifications preserve activity, or which payload pairs can be incorporated into the claimed structure without unacceptable levels of instability, loss of efficacy, or toxicity.
Although, certain claims identify trastuzumab, rituximab, anti-EGFR, anti-CD33, and CGKRK embodiments, the therapeutic data concern trastuzumab conjugates. Staudacher and Donaghy indicates that target expression, internalization, linker cleavage, payload permeability, and other design variables materially affect ADC performance. Accordingly, the absence of representative data or guidance for the other targeting moieties is material.
Claim 61 represents a separate scope. The claim requires administration of a compound
According to the claim 40, not administration of the antibody or antigen containing conjugate of the claim 48. Therefore, the claim encompasses treatment using a Formula (I) compound lacking the targeting antibody present in the therapeutic examples of the specification. The antibody may materially affect tumor localization, cellular uptake, pharmacokinetics, systemic exposure, and toxicity. The specification does not establish that the efficacy of a preformed trastuzumab conjugate can be reproduced by administering the corresponding nonconjugated Formula (I) compound.
The specification also does not explain how such a compound selectively reaches a tumor, whether and how its reactive moiety would react in vivo with an endogenous or separately administered biomolecule, or how nonspecific systemic reactions would be avoided.
Claim 61 further encompasses numerous biologically distinct cancers without the representative therapeutic data across the cancers, and any other biological data related to the biologically distinct cancers. "Cancer" as a proliferative disease is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, as seen, for example, in cancers of the breast, brain and salivary glands. They can occur in nearly much every part of the body through different molecular mechanisms. The prior art recognized that there has never been a compound capable of treating cancers generally. "The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally." (<https://www.uspto.gov/patents/laws/patent-examination-policy-mpep-staff-35-usc-112-1st-para-enablement#7f> ENABLEMENT DECISION TREE, Example F, situation 1). A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: "In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way". There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers, but the art has not established a compound effective against cancer generally , or even a majority of cancer.
Claim 62 requires a claim 40 compound and an antibody or antigen in a kit. To the extent that
the claimed kit encompasses subsequent conjugation or combined therapeutic use of those components, the specification does not provide sufficient guidance showing which combinations can be prepared and used successfully through the claimed scope.
Staudacher, Donaghy, and Sun supports that changes in the payload, linker, targeting moiety, target biology, conjugation design, and DAR can have substantial and interdependent effects on efficacy, pharmacokinetics, biodistribution, and safety. Thus, the limited examples disclosed in the specification fail to provide sufficient guidance across the entire claimed scope to reliably predict these effects, thereby requiring a person skilled in the art to engage in undue experimentation.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides useful guidance for preparing selected Formula (I) compounds, performing particular conjugation reactions, purifying and characterizing products and determining DAR. It also provides in vitro and limited in vivo data for selected trastuzumab/exatecan and trastuzumab/belotecan conjugates. These examples establish that particular embodiments can be made and used, but they do not establish enablement of the full genus unless they are representative of the scope of the claims or are accompanied by guidance permitting extension to materially different embodiments. (see MPEP 2164.02, 2164.03 and 2164.08)
For the compound genus, the specification does not explain how to select attachment sites on the broadly claimed active pharmaceutical ingredient moieties, determine whether a selected drug tolerates modification, resolve incompatible functional groups or predict whether two different payloads will remain stable and active after incorporation into the claimed structures. Although, the specification discloses particular synthetic routes for selected payloads, it does not provide generally applicable criteria for adapting those routes to the full range of anticancer, immune-stimulating, and immune-dampening agents encompassed by the claims.
This absence of guidance is material because the claimed payload classes differ in structure activity relationships, chemical sensitivities, solubility, potency, and toxicity. The specification provides no general criteria for distinguishing combinations that can be successfully prepared and retain the intended activity from unstable, inactive, insoluble, or unacceptably toxic.
For the conjugates, as discussed above, Staudacher identifies internalization, cleavage, payload permeability, and bystander activity as material determinants of efficacy. The specification does not provide a corresponding framework for selecting among the claimed targeting moieties, linkers and payloads or for predicting the behavior of the resulting conjugate. The disclosed trastuzumab/exatecan and trastuzumab/belotecan examples do not provide sufficient guidance for conjugates employing materially different antibodies, antigens, CGKRK, payload classes, or linker systems that are claimed.
In addition, in view of Sun, the DAR 4 working examples do not provide guidance throughout the DAR range recited in claim 59. The specification does not explain how to balance increased payload loading against aggregation, clearance, tissue distribution, efficacy, and tolerability. It also does not provide comparative examples or selection criteria showing how acceptable conjugates can be obtained at materially different DAR values, particularly near the upper limit of the claimed range of 200.
Accordingly, the instant specification lacks sufficient technical direction and representative working examples commensurate with the full scope of the claimed compounds, conjugates, treatment method, and kit. A person of ordinary skill in the art would be required to conduct substantial screening and optimization to determine which payload combinations, linker systems, targeting moieties, and DAR values yield compounds or conjugates that can be prepared and use with acceptable stability, activity, pharmacokinetics, and tolerability.
The quantity of experimentation necessary
Given the limited predictability of the art, the breadth of the claims, and the absence of sufficient guidance or representative working examples, a person having ordinary skill in the art would be required to engage in extensive experimentation to identify suitable attachment positions, determined whether the payloads tolerate modification, assess chemical and plasma stability, identify cleavage or activation products, evaluate solubility and aggregation, and confirm retention of biological activity.
Because the claims encompass structurally and mechanistically distinct payloads and mixed payload combinations, the disclosed exatecan and belotecan synthesis do not provide a standardized procedure applicable throughout the full scope of genus. Materially different payloads may require redesigned synthetic routes and independent determination of whether the resulting compounds remain stable and biologically active.
For materially different conjugates, the artisan would need to select a suitable target and targeting moiety, assess target expression and normal tissue distribution, determine internalization and trafficking, optimize the linker and conjugation conditions, and control product heterogeneity, n value, and DAR. The resulting conjugates would then require evaluation of antigen binding, internalization, payload release, plasma stability, aggregation, pharmacokinetics, biodistribution, efficacy, toxicity, maximum tolerated dose, and therapeutic index.
For the claim 61, the artisan would further need to determine whether a nonconjugated Formula (I) compound functions as a cancer therapy. This would require establishing its mechanism of tumor localization, any in vivo reactions to tumor and systemic exposure, payload release or activation, effective dose, route, and therapeutic window.
For the claim 62, to the extent the kit is intended for conjugation or combined therapeutic use, the artisan would need to determine which claim 40 compounds and antibodies or antigens are chemically and functionally compatible and under what conditions they can be successfully combined or conjugated.
Therefore, the required work would go beyond routine verification of the disclosed embodiments. It would require determining which payload combinations remain functional, which conjugates have acceptable pharmaceutical properties, which n value and DAR values are effective and tolerable, and which nonconjugated Formula (I) compounds can function as cancer treatments.
Accordingly, the instant claims 40-62 do not comply with the enablement requirement of §112, because practicing the claimed invention would require undue experimentation by a person of ordinary skill in the art without reasonable assurance of success.
Claim Rejections - 35 USC § 112, Written Description
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 40-46, 48-56 and 59-62 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 claim(s) contains 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by applicants. (see MPEP 2163.02)
An objective standard for determining compliance with the written description requirement is, "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed. (Emphasis added)
Further, the MPEP states that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. (see MPEP 2161.01)
For instance, generic claim language in the original disclosure does not satisfy the written description requirement if it fails to support the scope of the genus claimed. Ariad, 598 F.3d at 1349-50, 94 USPQ2d at 1171 ("[A]n adequate written description of a claimed genus requires more than a generic statement of an invention’s boundaries.") (citing Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1405-06); Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002) (holding that generic claim language appearing in ipsis verbis in the original specification did not satisfy the written description requirement because it failed to support the scope of the genus claimed); Fiers v. Revel, 984 F.2d 1164, 1170, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (rejecting the argument that "only similar language in the specification or original claims is necessary to satisfy the written description requirement").
As set forth in the en banc decision in Ariad Pharmaceuticals Inc. v. Eli Lilly and Company, 94 USPQ2d 1161 (Fed. Cir. 2010) at 1171, the court stated as follows:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus. Id. At 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. At 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 [25 USPQ2d 1601] (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001)). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
Claim 40 is drawn to a Formula (I) scaffold and defines R1-R4, and X1 by specified reactive, hydrophilic, peptide, or polymeric classes. Claims 41, 45 and 46 further narrow those components. However, R2 and R3 are each defined as an “the same or different active pharmaceutical ingredient moiety”. Claims 42-44 further characterize those moiety as an anticancer, immune stimulating or immune dampening agent moiety, optionally wherein R2 is an exatecan, belotecan, camptothecin, auristatin, Monomethyl auristatin E (MMAE) or a doxorubicin moiety. Claims 41, 45 and 46 additionally permit various reactive groups, hydrophilic components, polymers, and peptide sequences. Claims 48 is conjugate represented by Formula (I(a)) and permits the broadly defined R2 and R3 moieties to be combined with various R4, X1, X2 and R5 components. Claims 49-55 further encompass different payloads, peptide sequences, linkers, antibodies, antigens, and targeting moieties, including anti-EGFR antibodies, anti-CD33 antibodies, trastuzumab, rituximab, and CGKRK. Claim 59 and 60 further recite a DAR of 0.5 to 200 and an n values.
Therefore, the claimed subject matter encompasses combinations in which the payload, linker, reactive group, hydrophilic component, targeting moiety, and drug loading may each be independently varied. Thus, it is crucial to present a representative number of species that reflect the structural diversity of the claimed genus or demonstrate the structural characteristics common to that genus, but the current specification fails to meet this requirement.
Sun shows that changes in DAR materially affect ADC behavior, and reports that conjugates having average DAR values of approximately 9-10 exhibited more rapid clearance and greater hepatic accumulation than lower DAR conjugates, and that conjugates having DAR values of approximately 2-6 exhibited a better therapeutic index (abstract, and results and discussion section). Thus, DAR cannot reasonably treat as a freely variable numerical parameter independent of the antibody, target, payload, and linker. Claim 59 nevertheless encompasses a DAR ranges extending from 0.5 to 200, while the specification does not provide representative conjugates throughout the range, particularly near a DAR of 200.
Donaghy shows that ADC toxicity and therapeutic performance depend on the combined effects of the antibody, payload, linker, conjugation design, and drug loading, and changing one of these components may alter systemic stability, premature payload release, tissue exposure, hydrophobicity, aggregation, clearance, and organ specific toxicity. (ADC design, Toxicities of ADCs vs. standard treatments, and conclusion section) Thus, Donaghy supports that the substantial structural and functional diversity within the claimed genus.
Staudacher explains that ADC activity and bystander killing depend on the interaction among target binding, internalization, linker cleavage, and payload membrane permeability. (abstract and Is ADC internalisation required for bystander killing section) Staudacher further support that cleavable and non-cleavable linkers may require different mechanisms for payload release, and structurally related payloads may exhibit different bystander effects because of differences in membrane permeability.
The specification provides synthetic and biological disclosure for only a limited subset of the claimed subject matter, mainly particular trastuzumab conjugates containing exatecan or belotecan and particular linker structures. It does not provide representative examples involving other claimed payload classes, including auristatins, MMAE, doxorubicin, immune-stimulating agents, and immune dampening agents, or representative conjugates employing anti-EGFR antibodies, anti-CD33 antibodies, rituximab, antigens, or CGKRK across the claimed linker and loading ranges.
The specification does not provide representative conjugating the other payloads, including auristatins, MMAE, doxorubicin, immune-stimulating agents, and immune dampening agents, or representative conjugates employing anti-EGFR antibodies, anti-CD33 antibodies, rituximab, antigens, or CGKRK across the claimed linker and loading ranges.
Nor does the specification disclose structural features common to the claimed genus or a sufficient structure function relationship that would permit one of ordinary skill in the art to predict which combinations of payload, linker, targeting moiety, and drug loading combinations. In view of the structural diversity identified by Sun, Donaghy, and Staudacher, the limited trastuzumab/exatecan and trastuzumab/belotecan embodiments are not representative of the full scope of claims 40-46, 48-56 and 59-60.
Claim 61 additionally encompasses treatment of numerous biologically distinct cancers using the broad genus of Formula (I) compounds, and claim 62 encompasses a kit comprising the broad genus of Formula (I) compounds and the broad genus of an antibody or an antigen. However, as discussed above, the specification does not provide appropriate representative embodiments across the different active pharmaceutical ingredient classes, cancer types, an antibody, an antigen or a kit that possess therapeutic activity throughout the scope of the claims.
As set forth in the en banc decision in Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010), to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention at the time of filing. Specifically, the specification must describe the claimed invention in a manner understandable to a person of ordinary skill in the art in a way that shows that the inventor actually invented the claimed invention at the time of filing. Id.; Ariad, 598 F.3d at 1351, 94 USPQ2d at 1172. (see MPEP 2161.01).
Accordingly, in view of the breadth of the claimed combinations, the lack of representative examples, and the unpredictability of the art as discussed above, the limited disclosed specification does not reasonably convey to those skilled in the art that the inventors are in possession of the full scope of claimed combination therapies at the time of filing.
Conclusion
Claims 40-57 and 59-62 are rejected.
Claims 40, 42, 44, 48-51, 53 and 55-58 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEONG JONG KIM whose telephone number is (571)272-6918. The examiner can normally be reached 7:00am-3:30pm.
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/SEONG JONG KIM/Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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