Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1, 2 and 4-24 are pending in the application. Claim 1 is rejected. Claims 2 and 4-24 are withdrawn from further consideration.
Information Disclosure Statement
The Examiner has considered the Information Disclosure Statement(s) filed on April 6th, 2026.
Response to Amendment / Argument
On page 39 of the response filed March 16th, 2026, Applicant addresses the restriction and requests that examination extend “to another species such as those recited in claim 8…”. Instant claim 1 is rejected for lack of written description. Dependent claims will be considered for rejoinder once the Markush claim 1 is in condition for allowance.
Beginning on page 39 of the response, Applicant traverses the rejection of claim 1 under 35 USC 112(a). Regarding the Examiner’s statement of disclosed examples, Applicant refers to paragraphs [0154]-[0155] which are generic descriptions and not disclosed examples. Applicant further refers to examples of ADC conjugates through page 45 of the response. This issue is addressed in the rejection. The fact that parties have developed isolated examples where an antibody is first modified does not place a person of skill in possession of the myriad ways in which the instant structures are permitted to be conjugated.
On page 45 of the response, Applicant addresses an amendment to the specification, which does not affect the rejection over claim 1.
On pages 45 and 46 of the response, Applicant addresses the amendment to claim 1 to require conjugation to free thiols, which scope is addressed in the rejection.
Beginning on page 46-62 of the response, Applicant addresses conjugation methods found in the specification, which are not found persuasive for the reasons above including that they are only directed to using a final step of antibody conjugation (as opposed to the instantly claimed approach) and are significantly narrower in scope in terms of the types of connections embraced by claim 1.
On page 62 of the response, Applicant addresses preparation of antibodies and “detail production” corresponding to purchasing antibodies or known methods. The fact that a person of ordinary skill in the art can make an antibody for certain applications does not place a person of ordinary skill in the art in possession of all possible antibodies that could be applied in the instant embodiments especially since the instant claims are not limited to antibodies produced by any particular method. The instant claims embrace antibodies that could be generated specifically to address structural compatibility when attempting to use Applicant’s bis-linker strategy.
For these reasons, Applicant’s arguments are not found persuasive regarding the rejection under 35 USC 112(a).
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(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.
Claim 1 is 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.
Claim Scope (MPEP 2163(II)(A)(1)
MPEP 2163 outlines the methodology for determining adequacy of written description. MPEP 2163(II)(A)(1) instructs “For Each Claim, Determine What the Claim as a Whole Covers”.
The instant claim is directed to compounds where certain a portion is defined as including a “cell-binding molecule” as recited in the text of the claim. The instant formula (III) further encompasses substitution of the “cell-binding molecule” by groups embraced by the variables Z1, Z2, L1, L2, X’, Y’, n and m1. Regarding the scope of “cell-binding molecule,” the text of claim 1 recites that “a cell-binding molecule… is a molecule that is capable of binding to, complexing with, or reacting with a moiety of a target cell” and that it is an antibody or functional antibody fragment.
Disclosed Support (MPEP 2163(II)(A)(2))
MPEP 2163(II)(A)(2) instructs “Review the Entire Application to Understand How Applicant Provides Support for the Claimed Invention Including Each Element and/or Step”. The specification generally discusses the field of antibody-drug conjugates beginning on page 1 and discloses final product formula (I) on page 4 where a cytotoxic molecule is conjugated to a cell-binding agent/molecule. The specification discloses on page 10 that compounds of Formula (III) can be used to make compounds of Formula (I) “wherein two or more function groups of a cytotoxic molecule can react it simultaneously or sequentially to form Formula (I).” The specification generally discloses cell-binding agents beginning on page 52 where the disclosure refers to general methods of generating antibodies or known antibodies that have been previously reported (such as those disclosed on pages 56-59 of the specification). Any additional disclosures are related to antibodies that could be developed to target particular antigens or receptors such as those disclosed on pages 59-64.
The majority of the disclosure focuses on preparing conjugates by a different approach, i.e. by conjugating compounds of the following formula to a cell-binding molecule:
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See, for instance, page 35 of the specification. The disclosed examples beginning on page 130 each involve synthesizing a cytotoxic molecule (falling within the scope of formula (II)) followed by conjugation to a cell-binding molecule. Example 236 on page 226 appears to contain the only antibody-conjugate embodiments that were specifically made where each conjugate was prepared by reacting a compound of formula (II) (or analogous cytotoxic molecule substituted by a linker moiety) with “a her2 antibody”. There are no disclosed examples where a compound of formula (III) was prepared followed by conjugation to a cytotoxic molecule. Furthermore, each disclosed embodiment involves the reaction of a sulfur moiety on an antibody such as the following in Figure 5:
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Each example on pages 227-230 similarly contains an antibody bound through sulfur. The only disclosure towards generating compounds of formula (III) appears to be largely generic such as the disclosure on page 46 where Applicant states that compounds of the formula (IV) can be reacted independently, or simultaneously or sequentially. An embodiment where a compound of formula (IV) is reacted with a cell-binding molecule is presumably Applicant’s method for making compounds of formula (III).
As further noted in MPEP 2163(II)(A)(2), “Such a review is conducted from the standpoint of one of ordinary skill in the art at the time the application was filed (see, e.g., Wang Labs., Inc. v. Toshiba Corp., 993 F.2d 858, 865, 26 USPQ2d 1767, 1774 (Fed. Cir. 1993)) and should include a determination of the field of the invention and the level of skill and knowledge in the art.” A person having ordinary skill in the art would have generally been familiar with antibody-drug conjugates. Agarwal et al. (Bioconjugate Chem. 2015, 26, 176-192) provide the following general description of the art in the abstract:
[…] Despite the simplicity of this concept, generation of clinically successful ADCs has been very difficult. Over the past several decades, scientists have learned a great deal about the constraints on antibodies, linkers, and drugs as they relate to successful construction of ADCs. Once these components are in hand, most ADCs are prepared by nonspecific modification of antibody lysine or cysteine residues with drug-linker reagents, which results in heterogeneous product mixtures that cannot be further purified. […]
Furthermore, Agarwal et al. review biorthogonal conjugation methods and provide the following conclusions on page 188:
Thanks to advances in protein engineering, biorthogonal chemistry, and analytical methods, the field of site-specific ADC development is advancing rapidly. We can now covalently append a drug molecule to many sites on an antibody, but the chemistries for doing so are still few in number. Many of the site-specifically modified ADCs in coming years will likely be linked via maleimides, oximes, and triazoles, functional groups that bear the signatures of classic bioorthogonal reactions. As these functional groups see widespread use, we will also come to understand their strengths and limitations. […]
Agarwal et al. demonstrate that the state of the art with respect to generating conjugates is significantly more limited in terms of known methods of conjugation/reactions. Furthermore, Agarwal et al. state in the abstract that even the standard methods (which are limited) are typically performed using a final step of conjugating to the antibody as opposed to using compounds instantly claimed where an antibody is modified with a linker and can then be further conjugated.
Regarding the breadth instantly claimed (including any type of antibody, an incredible variety of linkers and potential utility with any type of conjugating partner), a person of ordinary skill in the art would expect each of the various embodiments would require separate considerations prior to implementation. McCombs et al. teach the following on page 344 regarding the identity of the linker (corresponding to the variable groups in Formula (III)):
The mechanism of drug release is an important consideration in linker selection. Non-cleavable linkers rely on degradation of the scaffold within the lysosome after internalization. Alternatively, cleavable linkers respond to physiological stimuli such as low pH, high glutathione concentrations, and proteolytic cleavage. Each strategy has inherent advantages and disadvantages, but ultimately the optimal combination of linker and conjugation chemistry must be uniquely tailored to correlate each unique facet: the antibody, the drug molecule, and the profile of the disease to be treated.
As noted above, there is no disclosure in the specification regarding any embodiments where a cell-binding molecule is first modified and subsequently conjugated to a therapeutically active molecule. The instant claim, however, embraces combinations of cell-binding molecules and linkers that according to McCombs et al. would each require unique tailoring.
Regarding the development of an appropriate cell-binding molecule, a person of skill in the art would recognize that developing workable targets is not straightforward. For instance, Tsuchikama et al. (Protein Cell, 2018, 9, 33-46, published online October 14th, 2016) teach the following difficulties on page 34:
Given the mechanism of action, the ideal antibody needs to have sufficient antigen affinity and specificity. However, antibodies with extremely high antigen affinity are known to lead to reduced efficiency of solid tumor penetration (Rudnick et. al., 2011). Thus, ADCs with high antigen affinity do not necessarily lead to high clinical efficacy. In addition, cell-surface antigens must be predominately expressed on target cells with minimal expression on healthy cells to achieve effective drug delivery and selective killing of tumor cells, which determines the therapeutic window. In this context, one may think tumor antigen density directly correlates to efficacy of ADCs. However, several studies suggest that the correlation between antigen density and ADC efficacy depends on the type of cancer cells (Polson et al., 2011; Kung Sutherland et al., 2013) due to varying internalization rate of each antigen after formation of a complex with an ADC molecule. While important to select a cancer cell-specific antigen, the prediction of total efficacy of ADCs based on the antigen expression level remains elusive (Damelin et. al., 2015).
Generally, the instant claim embraces modified antibodies where the antibody portion is minimally defined by a property of binding a particular target. The instant claim is therefore generic to modified antibodies where the antibodies are already known, currently unknown but that would be undesirable due to one of the factors discussed by Tsuchikama et al., as well as currently unknown but that would be highly desirable based on its particular properties and utility in a specific type of cancer.
Applicant has previously referred to alleged prior art disclosures that allegedly weigh in favor of possession (pages 36-38 of the response filed April 9th, 2024). The various citations, however, are limited in nature. The examples cited by Applicant represent tailored approaches discussed by McCombs et al. The fact that isolated examples have worked through the difficulties associated with conjugate formation for particular embodiments does not place a person of ordinary skill in the art in possession of the myriad types of structures embraced by the instant claims. Applicant notes on page 38 of the response filed April 9th 2024 that “information which is well known in the art need not be described in detail in the specification.” Even considering the examples cited by Applicant, they do not establish that methods of making structures instantly claimed would be considered well-known. The examples cited by Applicant do not involve structures where two functional groups on the cell-binding molecule form a larger cycle, i.e. where at least one instant dashed bond is a single or double bond. Having a linker react indiscriminately with any available cysteine residue does not entail the same considerations in having multiple residues on the cell-binding molecule form linkages with the same entity (in this case, the structure containing L1/L2/Z1/Z2/X’/Y’).
Determination of Sufficient Support (MPEP 2163(II)(A)(3))
MPEP 2163(II)(A)(3) instructs “Determine Whether There is Sufficient Written Description to Inform a Skilled Artisan That Inventor was in Possession of the Claimed Invention as a Whole at the Time the Application Was Filed”. This section of the MPEP further provides the following guidance:
Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
In this situation and as discussed above, Applicant has not disclosed examples reading on the scope of the instant claim. While the lack of any examples does not necessarily result in a lack of written description, MPEP 2163 (II)(A)(3)(a)(ii) discusses support for a generic claim as follows:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above).
The same section notes the following:
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
In this situation, Applicant provides no description of structures embraced by the instant claim and effectively relies upon the knowledge in the art regarding antibody-drug conjugates as well as general knowledge regarding antibody development. Applicant’s claim is generic to several features for which the necessary common attributes are lacking including the types of useful bond formations between the linker and the cell-binding molecule, the available functional groups to be used for further conjugation and the structures of cell-binding molecules possessing desirable binding properties for the various targets of the instant claim.
Specifically regarding antibodies, MPEP 2163(II)(A)(3)(a)(ii) discusses written description with respect to biomolecules as follows:
For some biomolecules, examples of identifying characteristics include a sequence, structure, binding affinity, binding specificity, molecular weight, and length. Although structural formulas provide a convenient method of demonstrating possession of specific molecules, other identifying characteristics or combinations of characteristics may demonstrate the requisite possession. As explained by the Federal Circuit, "(1) examples are not necessary to support the adequacy of a written description; (2) the written description standard may be met … even where actual reduction to practice of an invention is absent; and (3) there is no per se rule that an adequate written description of an invention that involves a biological macromolecule must contain a recitation of known structure." Falkner v. Inglis, 448 F.3d 1357, 1366, 79 USPQ2d 1001, 1007 (Fed. Cir. 2006); see also Capon v. Eshhar, 418 F.3d at 1358, 76 USPQ2d at 1084 ("The Board erred in holding that the specifications do not meet the written description requirement because they do not reiterate the structure or formula or chemical name for the nucleotide sequences of the claimed chimeric genes" where the genes were novel combinations of known DNA segments.). However, the claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
In the instant situation, the only disclosed examples of antibodies are those that have been previously reported in the art. Applicant provides no disclosure of antibodies that have been developed to target all of the various targets of, for instance, pages 61-64 of the specification.
For these reasons, instant claim 1 is deemed to lack adequate written description.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW P COUGHLIN whose telephone number is (571)270-1311. The examiner can normally be reached Monday - Friday, 10 am - 6 pm EST.
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/MATTHEW P COUGHLIN/Primary Examiner, Art Unit 1626
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