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
Applicant’s amendments and remarks, filed 11/19/2025, are acknowledged.
Claims 1-4, 6, 9, 11, 13, 14, 27, and 28 are canceled.
Claims 5 and 26 are amended.
Claims 5, 7, 8, 10, 12, and 15-26 are pending.
Claims 7, 8, 10, 12, and 15-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/26/23.
As such, claims 5 and 18-26 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Withdrawn Objections
The claim objections are withdrawn. Issues regarding minor informalities have been sufficiently addressed through amendments to the claims filed on 11/19/2025.
Withdrawn Rejections
Applicant’s arguments, see page 6, filed 11/19/2025, with respect to claim 27 rejected under 35 USC 112(d) as allegedly being of improper dependent form have been fully considered and are persuasive. The issue regarding improper dependent subject matter have been sufficiently addressed through amendments to the claim. Specifically, Examiner acknowledges that claim 27 is canceled, thus the rejection under 35 USC 112(d) is rendered moot.
Applicant’s arguments, see page 6, filed 11/19/2025, with respect to claims 5 and 18-27 rejected under 35 USC 112(b) as allegedly being indefinite have been fully considered and are persuasive. The issue regarding the claims comprising indefinite language have been sufficiently addressed through amendments to the claims. Further, Examiner acknowledges that claim 27 is canceled thus rendering the rejection moot. As such, the rejection under 35 USC 112(b) is withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 112(a) 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 5 and 18-26 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. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
Claim 5 is drawn to an antibody drug conjugate comprising at least one glucocorticoid receptor (GR) agonist or antagonist covalently conjugated to an anti-natural cytotoxicity triggering receptor 1 (NCR1) antibody that immunospecifically targets or binds an antigen of a specific marker of an innate lymphoid cell, wherein the specific marker is NCR1 and the innate lymphoid cell is a natural killer cell; wherein the at least one GR agonist or antagonist is selected from the group consisting of steroidal agonist, selective glucocorticoid receptor agonist, steroidal antagonist and nonsteroidal small molecule antagonist; wherein the antibody binds to the antigen with an affinity corresponding to a KD in the range of 10-7 M to 10-11 M; and wherein the at least one GR agonist or antagonist of the antibody drug conjugate modulates activity of GRs and glucocorticoid-programmed cell death protein 1 pathway, wherein said activity increases programmed cell death protein 1 expression and reduces interferon-gamma production in the natural killer cell relative to a natural killer cell that is not bound to the antibody drug conjugate.
Claim 18 is drawn to the antibody drug conjugate of claim 5, wherein the at least one GR agonist or antagonist is a steroidal agonist selected from the group consisting of fluticasone propionate, GSK 9027, methylprednisone, corticosterone, budesonide, ciclesonide, dexamethasone, hydrocortisone, prednisolone, loteprednol etabonate and mometasone furoate.
Claim 19 is drawn to the antibody drug conjugate of claim 5, wherein the at least one GR agonist or antagonist is a steroidal antagonist selected from the group consisting of beclometasone, betamethasone, budesonide, ciclesonide, flunisolide, fluticasone, mifepristone, mometasone, triamcinolone, ORG-34517, dexamethasone mesylate, dexamethasone oxetanone, deoxycorticosterone, CORT 0113083, CORT 00112716, RU-486, RU-43044, 11-monoaryl; 11,21 bisaryl steroid; 10β-substituted steroid; 11β-aryl conjugate of mifepristone and phosphorous-containing mifepristone analog.
Claim 20 is drawn to the antibody drug conjugate of claim 5, wherein the at least one GR agonist or antagonist is a nonsteroidal small molecule antagonist selected from the group consisting of an octahydrophenanthrene, a spirocyclic dihydropyridine, a triphenylmethane ether, a diaryl ether, a chromene, a dibenzyl aniline, a dihydroisoquinoline, a pyrimidinedione, an azadecalin, and an aryl pyrazolo azadecalin.
Claim 21 is drawn to the antibody drug conjugate of claim 5, wherein the at least one GR agonist or antagonist is a selective glucocorticoid receptor agonist selected from the group consisting of compound A, RU 24858, RU 24782, AL-438, ZK 216348, LDG-5552, BI 653048, compound 60, compound 15, MK-5932, mapracorat, fosdagrocorat and C108297.
Claim 22 is drawn to the antibody drug conjugate of claim 19, wherein the 11,21 bisaryl steroid is 11β-substituted steroid.
Claim 23 is drawn to the antibody drug conjugate of claim 20, wherein the aryl pyrazolo azadecalin is an 8a-benzyl isoquinolone.
Claim 24 is drawn to the antibody drug conjugate of claim 5, wherein the GR agonist is selected from the group consisting of fluticasone propionate, GSK 9027, methylprednisolone, corticosterone and mometasone fuoate.
Claim 25 is drawn to the antibody drug conjugate of claim 24, wherein the GR agonist is corticosterone.
Claim 26 is drawn to an antibody drug conjugate comprising corticosterone covalently conjugated to an antibody directed against a natural cytotoxicity triggering receptor 1 (NCR1), wherein the antibody immunospecifically binds to NCR1 on a natural killer cell with an affinity corresponding to a KD in the range of 10-7 M to 10-11 M; and wherein the corticosterone of the antibody drug conjugate modulates activity of glucocorticoid receptors, wherein said activity increases programmed cell death protein 1 expression and lowers interferon-gamma production in the natural killer cell relative to a natural killer cell that is not bound to the antibody drug conjugate.
The specification provides examples that show the control of NCR1+ innate lymphoid cells (ILCs) function by glucocorticoids is tissue specific (see pg. 30, lines 3-4), NCR1+ ILC3s and their responsiveness to glucocorticoids do not have a major impact on the immune response to murine cytomegalovirus (MCMV) infection (see pg. 30, lines 13-15), and endogenous glucocorticoids induce PD1 expression on natural killer (NK) cells which leads to the control of IFN-γ production of these cells during MCMV infection (see pg. 33, lines 21-24). Particularly, the specification discloses that corticosterone did not increase IFNγ production in NK cells (see pgs. 29-30), but was able to induce PD1 expression on NK cells in a dose-dependent manner when in combination with IL-15 + IL-18 (see Fig. 4b; pg. 32, lines 20-22).
There are several issues with written description for the elected invention. First, the specification fails to teach of an ADC comprising at least one GR agonist or antagonist covalently conjugated to an anti-NCR1 antibody that immunospecifically targets or binds an antigen of a specific marker of an innate lymphoid cell, wherein the innate lymphoid cell is a natural killer cell as described by the claims. Specifically, the specification fails to adequately describe the anti-NCR1 antibodies and GR modulators that are capable of the required functions. Second, the specification fails to demonstrate possession of a representative number of species of GR agonists and antagonists conjugated to anti-NCR1 antibodies. Third, the specification fails to demonstrate an ADC comprising more than one GR agonist or antagonist that also induce programmed cell death protein 1 expression and reduce interferon-gamma production in the natural killer cell. Lastly, the specification fails to adequately describe a “phosphorus-containing mifepristone analog.”
In regard to the instant claims, the claims are directed to an ADC that is defined entirely by function (binding; modulation). See MPEP § 2163(I)(A) which states:
"The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.”
As currently presented, the claims describe the ADC solely by function, i.e. binding/targeting NRC1 of an innate lymphoid cell conjugated to an agonist/antagonist of glucocorticoid receptor wherein the antibody is covalently attached to the agonist/antagonist of a glucocorticoid receptor and wherein the antibody binds to the antigen with an affinity corresponding to a KD of 10-7 M to 10-11 M and induce programmed cell death protein 1 expression and reduce interferon-gamma production in the natural killer cell. Thus, the genus of ADCs are extremely broad because the claims recite generic and incompletely described ADCs. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed ADC without adequate descriptions of its component parts or overall makeup. The generically claimed ADC comprising an anti-NCR1 antibody that is conjugated to an agonist or an antagonist of glucocorticoid receptor does not impart enough structural information to permit one of ordinary skill in the art to reasonably recognize or understand that Applicant was in possession of the full scope of the genus of ADCs recited in the claims. For instance, without knowing the structure of the anti-NRC1 antibody of a natural killer cell, one would not be able to adequately describe the claimed ADC. Therefore, the specification does not provide adequate written description to identify the broad and variable genus of ADCs because, inter alia, the specification does not disclose a correlation between the necessary structure of the ADC and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function.
Although the specification discloses corticosterone did not increase IFNγ production and induced PD1 expression on NK cells in a dose-dependent manner when in combination with IL-15 + IL-18, the claims are not limited to this GR modulator, and are inclusive of any ADC comprising any GR agonists or antagonists conjugated to any anti-NCR1 antibodies with the claimed functions. There are hundreds, if not thousands, of possible ADCs comprising any GR agonist or antagonist and anti-NCR1 antibody encompassed by the claims. Thus, the claims encompass a vast genus of GR modulators and antibodies that have the claimed function (i.e., bind or target NCR1). However, the specification provides limited guidance on the structure required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of antibodies because, inter alia, the specification does not disclose a correlation between the necessary structure of the substance and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Although the term antibody does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
The instant claims do not fully describe the required method, or present any form of specific threshold or other standards that would allow the method to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of the claimed antibodies, claimed only be a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous antibodies had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of antibodies claimed only by a partial structure and functional characteristic(s). Thus the method described by the instant specification encompasses an overly broad genus, and there is no correlation between the steps of the method, the structure of the antibody, and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of all IL-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to Abbvie above. First, the claims clearly attempt to define the genus of anti-NCR1 antibodies by the function of having a recited dissociation constant and ability to immunospecifically target or bind an antigen of a specific marker of a natural killer cell. As noted by Abbvie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no description of any specific embodiments of the anti-NCR1 antibody genus in the specification based upon which one of skill in the art would conclude that applicant has identified a representative number of species that have the recited functions. Further, the specification discloses no specific antibody structures to correlate with the required functions.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "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. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed antibodies, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
It is established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. Paul (Fundamental Immunology, 3rd Edition, Raven Press, New York, Chapter 8, pages 292-295, 1993; previously submitted with the action mailed 02/27/2024) teaches that the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (See pages 293-295). While some publications acknowledge that CDR3 is important for antigen binding, the conformations of other CDRs as well as the framework are equally important in antigen binding. For example, MacCallum et al. (Journal of Molecular Biology, 262:732-745, 1996; previously submitted with the action mailed 02/27/2024) analyzed antigen-contacting residues and combining site shape of various antibodies and state that although CDR3 of the heavy chain and light chain dominate, a number of residues outside of the standard CDR definitions make antigen contacts (See page 733). MacCallum et al. teach that antigens tend to bind to the antibody residues located at the center of the combining site where the six CDRs meet (See abstract and page 742) and less central CDR residues are only contacted by large antigens (See page 733 and 735). MacCallum et al. further teach that non-contacting residues are important in defining "canonical" backbone conformations.
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is further underscored by Casset et al. (Biochemical and Biophysical Research Communications, 307:198-205, 2003; previously submitted with the action mailed 02/27/2024), which discuss the importance of multiple CDRs in antigen contact. Casset et al. teach that all antibodies have six CDR residues, all of which are more or less involved in antigen recognition (See page 199). Casset et al. teach that peptide mimetics of antibody combining sites have previously only targeted CDR H3, since this CDR is typically at the center of most, if not all, antigen interactions; however, this strategy is flawed since other CDRs play an important role in the recognition of antigen (See page 199). Casset et al. construct a peptide mimetic of an anti-CD4 monoclonal antibody, containing antigen contact residues from five CDR regions, except L2 and additionally using a framework residue located just before the H3 and show that the peptide has high binding to CD4, thus signifying the contribution of multiple CDRs, and not a single CDR, in antigen recognition (See page 202 and Figure 4).
Vajdos et al. (Journal of Molecular Biology, 2002 Jul 5;320(2):415-28; previously submitted with the action mailed 02/27/2024) additionally teaches that, “... Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.
Further, Sela-Culang et al. 2013 (The structural basis of antibody-antigen recognition; Frontiers in Immunology 4(302):1-13; previously submitted with the action mailed 02/27/2024) teach the hypervariable loops within the variable domains of antibody polypeptides are widely assumed to be responsible for antigen recognition while the constant domains are believed to mediate effector activation, but that recent analysis indicates that their clear functional separation between the two regions is an over-simplification (see abstract). Sela-Culang et al. teach some residues within the CDRs may not participate in antigen binding and some residues outside the CDRs (e.g. in framework regions and in the constant domains) often contribute critically to the integration with the antigen (see abstract). Sela-Culang et al. teach understanding the role of each structural element is essential for successful engineering of binding polypeptides (e.g. page 2, left column). Sela-Culang et al. teach almost all of the residues predicted to be part of an epitope may be considered as correct predictors as they will bind to some antibodies but also are false predictors as they don’t bind to the others and accordingly that predicting that a residue is not in an epitope may be either a true negative or a false negative depending on the anybody considered (page 2, right column). Sela-Culang et al. teach each CDR has its own unique amino-acid composition different from the composition of the other CDRs and that each CDR has a unique set of contact preferences favoring certain amino acids over others (page 5-6, bridging). Sela-Culang et al. teach the combined action of all six CDRs is the evolutionary response of the immune system that enables the antibody polypeptide to recognize virtually any surface patch on the antigen (page 6).
The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2; previously submitted with the action mailed 05/20/2025), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed proteins and peptides of the ADC, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9; previously submitted with the action mailed 05/20/2025), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990; previously submitted with the action mailed 03/08/2023) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988; previously submitted with the action mailed 02/27/2024) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98; previously submitted with the action mailed 05/20/2025) teach that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400; previously submitted with the action mailed 03/08/2023) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668; previously submitted with the action mailed 05/20/2025), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937; previously submitted with the action mailed 03/08/2023). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed antibody drug conjugates could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
The state of the art regarding subclass differences in affinity and kinetic constants as determined by surface plasmon resonance is discussed by Cooper et al. (Molecular Immunology, 1994; 31(8):577-584; Abstract only; previously submitted with the action mailed 02/27/2024). Cooper et al. teach that variable domain-identical antibodies exhibit IgG subclass related differences in affinity and kinetic constants (See Abstract). Cooper et al. teach that differences in heavy chain constant domains can significantly influence apparent functional affinity for multivalent antigen; differences in constant heavy domains can alter both association and dissociation rate constants for interactions between IgG antibodies and multivalent antigen; and these effects of constant heavy domains depend on epitope density (See Abstract). Given the variability in differences in affinity and kinetic constants based on antibody subclass, it is unclear if all anti-NCR1 antibodies would have the high affinity binding function required by the claims. Therefore, one would not conclude that Applicant possessed the genus of antibodies encompassed by the claims.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all anti-NCR1 antibodies which have the required KD.
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
Additionally, the ADC of the claims comprises an agonist or antagonist of glucocorticoid receptor. The specification teaches that a glucocorticoid receptor antagonist is any compound, natural or synthetic, that blocks, suppresses, or reduces (including significantly) the biological activity of glucocorticoid receptor or to any compound that inhibit GR gene expression (p. 3, lines 23-26). The specification also teaches that a GR agonist is any compound, natural or synthetic, that enhances/increases (including significantly) the biological activity of GR or to any compound that inhibit GR gene expression (p. 6, lines 3-6). Particularly, the specification teaches that the GR agonists or antagonists of the claimed ADC is not limited to: small organic molecule, antibody or antibody fragment, a polypeptide or an activator of GR expression (see pgs. 4 and 6). By these definitions, the ADC recited in the claims is extremely broad, generic, and variable because it encompass a wide genus of compounds that modulates the GR in some capacity.
Issues regarding inadequate description of antibodies/proteins are discussed above. Furthermore, regarding GR agonists or antagonists that are small molecules of a particular protein target, the prediction of binding to a target, much less the inhibitory activity, is highly unpredictable. According to Guido et al. (Curr Med Chem. 2008;15(1):37-46; previously submitted with the action mailed 05/20/2025), accurately predicting the binding affinity of new drug candidates remains a major challenge in drug discovery (see page 37). There are a vast number of possible compounds that may bind any particular target, many of which have likely not been discovered. Relying on virtual screening also lends unpredictability to the art regarding identification of molecules that would be capable of the required functions of the instant claims. Guido et al. teach that there are two main complex issues with predicting activity for a small molecule: accurate structural modeling and/or correct prediction of activity (see page 40). As taught by Clark et al. (J. Med. Chem., 2014, 57 (12), pp 5023–5038; previously submitted with the action mailed 05/20/2025), even when guided by structural data, developing selective structure-activity relationships has been challenging owing to the similarities of the enzymes (see page 5028). Therefore, it is impossible for one of skill in the art to predict that any particular encompassed small molecule therapeutic would function to inhibit a particular protein, especially a particular protein family member, or treat disease.
Regarding GR agonists or antagonists that are nucleic acid-based therapeutics, the efficacy of any possible DNA or RNA based therapeutic modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence the expression or function of any target. As taught by Aagaard et al. (Advanced Drug Delivery Reviews 59 (2007) 75–86; previously submitted with the action mailed 05/20/2025), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems and therapeutics that are efficient at low doses (see page 79), the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses (see page 79), competition with cellular RNAi components (see page 83), the side effect of suppressing off targets (see page 80), and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al. (Leukemia and Lymphoma (1997) Vol. 24. pp. 267-281; previously submitted with the action mailed 05/20/2025) teach that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three-dimensional RNA structures (see page 269), while DNA-targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins (see page 269). These references demonstrate that variation in RNA or DNA based therapeutics will often dramatically affect the biological activity and characteristics of the intended therapeutic. McKeague et al. (J Nucleic Acids. 2012;2012:748913. Epub 2012 Oct 24; previously submitted with the action mailed 05/20/2025) teach that aptamers have particular challenges because unlike antibodies or molecular imprinted polymers, their tertiary structure is highly dependent on solution conditions and they are easily degraded in blood. Further, they have less chemical diversity than other antagonist molecules (see page 2), and have issues associated with determining the Kd measurements for a given molecule (see page 13).
Given the teachings of Aagaard et al, Warzocha et al, and McKeague et al, the claimed nucleic acid therapeutics could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed nucleic acid based therapeutic, such as oligonucleotide aptamers, RNAi molecules and antisense oligonucleotides, would function to decrease expression or function of a target gene or protein, or treat disease.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA or proteins, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all ADCs.
Furthermore, the state of the art regarding GR modulators is described by Meijer et al. (Annales d’Endocrinologie 79 (2018) 107–111; previously submitted with the action mailed 03/08/2023). Meijer et al. teach that both agonism and antagonism of the GR may be beneficial in disease, but given the wide expression of the receptor and involvement in various processes, beneficial effects are often accompanied by unwanted side effects (see Abstract). Meijer et al. also teach that GR agonism is a very common goal in inflammation, whereas antagonism of GR is currently being used in a subset of patients with Cushing’s Disease (pg. 3, col. 2). Meijer et al. teach of two selective GR modulators, CORT108297 and CORT118335, that are effective in modulating GR and lack affinity for androgen and progesterone receptors which is often a consequence of mifepristone, a known GR antagonist (pg. 3, col. 2). CORT108297 induces a pattern of coactivator interactions that is intermediate to that of the full agonist dexamethasone and the antagonist mifepristone which suggest efficacy (that is: agonism) in processes that depend on those interactions that do occur and antagonism for the processes that simply cannot be induced for lack of interaction (pg. 2, col. 2). CORT108297 and CORT118335 differ subtly in the interactions, thus they are both expected to act as selective GR modulators, but with a different molecular profile (pg. 2, col. 2). Therefore, the state of the art teaches of at least four GR modulators that comprise different molecular profiles and interactions/functions.
Lastly, Applicants have not shown possession of a representative number of species of ADCs. As noted above, the claims are generic for the components of the ADC. While claims 18-21 narrow the genus of GR agonists/antagonists to specific species, the Applicant has not demonstrated possession of an ADC comprising these species of GR agonists/antagonists. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "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. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed ADCs. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of recombinant proteins as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Applicant’s Arguments
Applicant traverses the written description rejection (see pages 6-8 of the Remarks filed on 11/19/2025).
The Examiner is of the position that the application fails to describe and provide a working example of the claimed genus of GR agonists and antagonists and NCR1 antibodies. The Applicant respectfully disagrees. MPEP 2163 states that "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." It is further stated that" The description need only describe in detail that which is new or not conventional." (emphasis added; MPEP 2163). As discussed below, GR agonists and antagonists and NCR1 antibodies are not new and are conventional in the art… In the present case, the claims encompass GR agonists and antagonists and NCR1 antibodies that were well known in the art. Indeed, pages 6-10 of the application as filed provides numerous examples of GR agonists and antagonists, many of which are recited in dependent claims 18-25. Independent claim 26 is specifically limited to corticosterone. Further, the previous response included five product sheets describing various anti-NCR1 antibodies that are commercially available. The Examiner responded to this evidence by indicating that such evidence must predate the present application. It is respectfully submitted that such antibodies were indeed commercially available prior to the present application. In addition, submitted herewith are journal articles published before the filing of the present application which also disclose such anti-NCR1 antibodies. Moreover, as disclosed in the paragraph bridging pages 13-14 of the application, techniques for conjugating molecules to antibodies are well-known in the art. As discussed above, it is not required to reduce to practice the invention in order to satisfy the written description requirement. Accordingly, it is clear that one of ordinary skill in the art would recognize that the inventor was in possession of the antibody drug conjugates of the claimed invention.
Response to Arguments
Applicant's arguments filed 11/19/2025 have been fully considered but they are not persuasive.
Examiner acknowledges that production of antibodies that bind to an antigen is generally known in the art. However, the recited NCR1 antibodies must possess another specific function, namely a specific binding affinity. In addition, the GR agents are not limited to any particular molecule type, and the GR agents must possess multiple functions in addition to the binding specificity, such as providing agonist or antagonist activity and modulating the activity of GRs and glucocorticoid-programmed cell death protein 1 pathway. As stated above, Applicant has not demonstrated possession of this very broad genus of claimed conjugates that are described only according to their named functions. The MPEP clearly states that 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 Abbvie, Fed. Cir. 2014). In Abbvie, the Court held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of all IL-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. This example is nearly identical to the present case. Applicant is trying to describe the antibody only by the antigen it targets. Applicant is also trying to describe the GR agonist or antagonist entirely by its function (i.e., modulate activity of GRs and glucocorticoid-programmed cell death protein 1 pathway and increases programmed cell death protein 1 expression and reduces interferon-gamma production in the natural killer cell). While the specification may list glucocorticoid agonists and antagonists with specific agents, these agents are merely examples and the specification fails to demonstrate that Applicant was in possession of the large genera of antibody drug conjugates that resulted in increases programmed cell death protein 1 expression and reduces interferon-gamma production in a natural killer cell. One of skill in the art would not be apprised that Applicant was in possession of the large genera of antibody drug conjugates with the claimed functions.
While Applicant is entitled to use functional language in the description of claimed agents, according to MPEP 2163, an invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. This matches the facts here. The claims require specific functionality for the claimed antibody drug conjugates but neither the instant disclosure, nor the art, provide description of the corresponding structure for that functionality or a representative number of species for the agents/components. For example, the anti-NCR1 antibody of the conjugate is defined by its binding specificity and its binding affinity. In both the base claims and the dependent claims, for at least one agent/component in each claim, the claims only describe what the agent/component does, not what the agents/components are. While the agent/component of the GR agonist or antagonist of the claimed drug conjugate is described like in dependent claims 18-26, the anti-NCR1 antibody of the drug conjugate is not adequately described, and in fact lacks any description except for its functional properties. Even when given possible sequences from which to select antibody that would bind to NCR1, the question remains about which one(s) of the encompassed antibodies would actually perform the other claimed functions. While methods to identify the antibodies or agonists/antagonists with the required function may be routine in the art, the fact that any experimentation is required to figure out exactly what is encompassed necessarily means that applicant has not sufficiently described the claimed subject matter.
There are thousands of possible antibody drug conjugates encompassed by the instant claims. One of skill in the art could not immediately envisage the encompassed species in each genus from the guidance provided in the instant specification and claims. Applicant has not supplied a single species of antibody drug conjugates, which comprises corticosterone or any other GR agonist or antagonist, and any anti-NCR1 antibody. This encompasses an extremely broad genus of conjugates with a specific function, for which no correlating structure is provided.
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 "merely by clearly describing one embodiment of the thing claimed." LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005). Describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene' s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described.").
The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen Inc., v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Further, arguments relating to the isolation of an antibody with specific characteristics may be more appropriately directed to the invention' s enablement, since the method of isolating would detail how to make the invention. However, the enablement of the invention has not been rejected by the Examiner.
Lastly, Applicant asserts that product sheets describing various anti-NCR1 antibodies that are commercially available was submitted, but those product sheets were not properly identified in an IDS. However, with respect to these anti-NCR1 antibodies, MPEP 2163 is very clear that any description must be present at the time of invention – i.e. in the originally-filed specification, or in the art at the time of filing - (“a satisfactory description may be found in originally-filed claims or any other portion of the originally-filed specification. See In re Koller, 613 F.2d 819, 204 USPQ 702 (CCPA 1980)”). While Applicant can offer newly available data/evidence for enablement rejections, Applicant cannot do the same for written description especially if these examples were not available in the prior art at the time of filing. Furthermore, Applicant’s assertion that anti-NCR1 antibodies journal articles published before the filing of the present application were submitted is not accurate. Applicant has not provided any information to be considered in either a declaration or IDS with an explanation that identifies any specific encompassed antibodies that possess the required functions.
As such, the written description rejection is maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 5, 18-20, and 22-27 are rejected under 35 U.S.C. 103 as being unpatentable over Pan et al. (US 2011/0269728 A1, publication date: 11/03/2011), as evidenced by Xing et al. (BMC Immunology (2015) 16:39) and Quatrini et al. (J. Exp. Med. 2017 Vol. 214 No. 12 3531–3541), and further in view of Glasner et al. (Scientific Reports volume 7, Article number: 13090 (2017)), Yossef et al. (PLoS ONE 10(2): e0118936; publication date: 02/26/2015), and Brandish et al. (WO 2017/062271 A2; publication date: 04/13/2017).
Pan et al. teach of developing ADC for immunotherapeutics comprising a glucocorticoid antagonist wherein the drug relies on the use of immune effector cells and molecules to target and destroy cancer cells (see [0186]). Pan et al. teach that glucocorticoids exert their pharmacological effects by regulating gene transcription after the formation of a complex with the glucocorticoid receptor (GR) (see [0088]). Pan et al. teach that antagonizing GR activation with a GR antagonist, such as mifepristone, reverses cell survival signaling pathways initiated by the GR and potentiate apoptosis in response to cell stressors (see [0090]). In addition, Pan et al. teach the immune effector may be an antibody specific for some marker on the tumor cell such as cytotoxic T cells and natural killer (NK) cells (see [0186]).
In regard to claim 18, Pan et al. recite utilizing glucocorticoid receptor antagonists such as budesonide and ciclesonide (see [0043]). Pan et al. teach that naturally occurring as well as synthetic steroidal glucocorticoids (e.g., cortisol and dexamethasone) have been widely used for the treatment of acute and chronic inflammatory and immune disorders (see [0087]).
In regard to claim 19, Pan et al. teach of treating cancer with a glucocorticoid antagonist, mifepristone (see [0209]). Additionally, the glucocorticoid antagonist can be CORT 0113083, CORT 0112716, dexamethasone oxetanone, deoxycorticosterone, flunisolide, fluticasone, mometasone, triamcinolone, ORG-34517, 11β-aryl conjugate of mifepristone, and phosphorous-containing mifepristone analog (see [0161]).
In regard to claims 20 and 22-23, Pan et al. disclose that the glucocorticoid receptor antagonists can be chromene, 11β-substituted steroids, an 8a-benzyl isoquinolones, dibenzyl anilines, dihydroisoquinoline, pyrimidinediones, azadecalins, and aryl azadecalins (see [0161]).
Pan et al. fails to teach of an ADC comprising an anti-NCR1 antibody.
However, Glasner et al. teach that NK cells are important first line of defense innate lymphocytes (pg. 1, para. 1). Glasner et al. teach that NK cells are capable of recognizing and eradicating various cancers efficiently, however are not subject to many complications that may obstruct T-cell based immunotherapies (p. 5, para. 1). Glasner et al. teach that NK cells employ activating receptors like the natural cytotoxicity receptors (NCRs: NKp30, NKp44, and NKp46), of which only NKp46 has a mouse orthologue (NCR1), to eliminate abnormal cells (see Abstract). In particular, NKp46/NCR1 is considered a selective marker for NK cells, although it is also found on a subset of ILCs, where it appears to be without function (see Abstract). Glasner et al. found that overexpression of NCR1 in NK cells increased NK cell immunity (see Abstract). Glasner et al. also teach that NKp46 is involved in Type I and Type II diabetes (pg. 1, para. 2).
With respect to the limitation of an antibody that binds to NCR1 with an affinity corresponding to a KD of about 10-7M to 10-11M, Yossef et al. describe developing monoclonal antibodies that target murine NKp46, NCR1 (see Abstract). Specifically, Yossef et al. disclose of antibody NCR1.15 which demonstrated binding affinity of 1.06E-08 M to NCR1 and only targeted NCR1 in murine NK cells (see pg. 5 and Fig. 1C). Yossef et al. disclose that the NCR1.15 antibody had inhibited development of diabetes, an autoimmune disease (see pg. 2), in the LDSTZ model and in NOD mice (see pg. 11; Figs. 4 and 6).
Lastly, with respect to the limitation that the antibody is covalently attached to the agonist or an antagonist of glucocorticoid receptor, Brandish et al. describe antibody drug conjugates for anti-inflammatory applications (see entire document). Specifically, teach of antibody drug conjugates wherein the antibody is conjugated to an anti-inflammatory therapeutic agent via a phosphate-based linker that is covalently attached to the antibody and the anti-inflammatory therapeutic (see pg. 25, lines 5-31). Brandish et al. further describes that the anti-inflammatory therapeutic agent comprise of glucocorticoid receptor agonists, such as cortisol and dexamethasone (see pg. 29). Brandish et al. found that the linkers of their invention provide greater solubility relative to disulfide linkers, cathepsin B-cleavable linkers, esters and acid-sensitive linkers; enable the release of the payload in its parent or unadulterated form; and, provide superior blood stability relative to esters and disulfides (see pg. 28; Figs. 2 and 4A-6D). Brandish et al. also recites other types of linkers in antibody drug conjugates and indicates that linkers should be sufficiently stable while in circulation to allow delivery of the intact antibody drug conjugate to the target cell but also labile to allow release of the drug moiety from the antibody drug conjugate once inside the target cell (see pg. 27, lines 3-20). Brandish et al. teach that the ADC of their invention can be used to treat conditions such as diabetes, cancer, or inflammatory disease (see pg. 24, lines 4-8).
Therefore, it would have been obvious to one of ordinary skill in the art at the time of the present invention to modify the ADC described by Pan et al. to develop the ADC of the present invention. One would be motivated to do so as NCR1 is a marker for NK cells and ILCs, and NK cells are capable of recognizing and eradicating various cancers efficiently. Also, as demonstrated by Glasner et al., overexpression of NCR1 in NK cells displayed increased NK cell cytotoxicity which will be beneficial in immunotherapeutics, especially for patients with diabetes as NKp46/NCR1 is involved in the development of Type I and Type II diabetes. This is supported by Yossef et al. who demonstrated that an antibody that targets NCR1 with an affinity between 10-7M to 10-11M (specifically, 1.06E-08 M) inhibited the development of diabetes in mice models. Lastly, one of skill in the art would be motivated to develop an ADC, using the antibody of Yossef et al., that is covalently attached to an anti-inflammatory agent such as a GR antagonist (as taught by Pan et al.) or GR agonist (as taught by Brandish et al.) as Pan et al. teach that glucocorticoid steroids (GR antagonists and agonists) are widely used for the treatment of inflammatory and immune conditions/disorders. While Brandish et al. focused on GR agonists, GR antagonists are also to be considered as they also demonstrate anti-inflammatory properties. Further, while Pan et al. does not explicitly state that these glucocorticoid receptor antagonists induce programmed cell death protein 1 expression and reduce interferon-gamma production in the natural killer cell, these properties are inherent of GR agonists and antagonists as evidenced by Xing et al. (see Abstract) and Quatrini et al. (see Abstract). Specifically, Quatrini et al disclose that corticosterone inhibited IFN-gamma production by spleen NK cells (see pg. 3533, right col.; Fig. 2C).
Therefore by developing an ADC comprising an anti-NCR1 antibody that has demonstrated therapeutic benefit for autoimmune disorders (e.g., diabetes) conjugated to an anti-inflammatory agent (e.g., GR antagonist or agonist such as corticosterone) would be beneficial to those suffering from an inflammatory and/or immune condition such as diabetes or inflammatory breast cancer. Also by linking the anti-inflammatory agent to the antibody covalently, it allows the ADC to be stable while in circulation while also allowing easy release of the antibody once the ADC reaches the target.
Claims 5 and 18-27 are rejected under 35 U.S.C. 103 as being unpatentable over Pan et al. (US 2011/0269728 A1, publication date: 11/03/2011), as evidenced by Xing et al. (BMC Immunology (2015) 16:39) and Quatrini et al. (J. Exp. Med. 2017 Vol. 214 No. 12 3531–3541), Glasner et al. (Scientific Reports volume 7, Article number: 13090 (2017)), Yossef et al. (PLoS ONE 10(2): e0118936; publication date: 02/26/2015), and Brandish et al. (WO 2017/062271 A2; publication date: 04/13/2017) as applied to claims 5, 18-20, and 22-27 above, and further in view of De Bosscher (Journal of Steroid Biochemistry & Molecular Biology 120 (2010) 96–104).
Pan et al. teach of developing ADC for immunotherapeutics comprising a glucocorticoid antagonist wherein the drug relies on the use of immune effector cells and molecules to target and destroy cancer cells (see [0186]). Pan et al. teach that glucocorticoids exert their pharmacological effects by regulating gene transcription after the formation of a complex with the glucocorticoid receptor (GR) (see [0088]). Pan et al. teach that antagonizing GR activation with a GR antagonist, such as mifepristone, reverses cell survival signaling pathways initiated by the GR and potentiate apoptosis in response to cell stressors (see [0090]). In addition, Pan et al. teach the immune effector may be an antibody specific for some marker on the tumor cell such as cytotoxic T cells and natural killer (NK) cells (see [0186]).
In regard to claim 18, Pan et al. recite utilizing glucocorticoid receptor antagonists such as budesonide and ciclesonide (see [0043]). Pan et al. teach that naturally occurring as well as synthetic steroidal glucocorticoids (e.g., cortisol and dexamethasone) have been widely used for the treatment of acute and chronic inflammatory and immune disorders (see [0087]).
In regard to claim 19, Pan et al. teach of treating cancer with a glucocorticoid antagonist, mifepristone (see [0209]). Additionally, the glucocorticoid antagonist can be CORT 0113083, CORT 0112716, dexamethasone oxetanone, deoxycorticosterone, flunisolide, fluticasone, mometasone, triamcinolone, ORG-34517, 11β-aryl conjugate of mifepristone, and phosphorous-containing mifepristone analog (see [0161]).
In regard to claims 20 and 22-23, Pan et al. disclose that the glucocorticoid receptor antagonists can be chromene, 11β-substituted steroids, an 8a-benzyl isoquinolones, dibenzyl anilines, dihydroisoquinoline, pyrimidinediones, azadecalins, and aryl azadecalins (see [0161]).
Further, while Pan et al. does not explicitly state that these glucocorticoid receptor antagonists induce programmed cell death protein 1 expression and reduce interferon-gamma production in the natural killer cell, these properties are inherent of GR agonists and antagonists as evidenced by Xing et al. (see Abstract) and Quatrini et al. (see Abstract). Specifically, Quatrini et al disclose that corticosterone inhibited IFN-gamma production by spleen NK cells (see pg. 3533, right col.; Fig. 2C).
Glasner et al. teach that NK cells are important first line of defense innate lymphocytes (pg. 1, para. 1). Glasner et al. teach that NK cells are capable of recognizing and eradicating various cancers efficiently, however are not subject to many complications that may obstruct T-cell based immunotherapies (p. 5, para. 1). Glasner et al. teach that NK cells employ activating receptors like the natural cytotoxicity receptors (NCRs: NKp30, NKp44, and NKp46), of which only NKp46 has a mouse orthologue (NCR1), to eliminate abnormal cells (see Abstract). In particular, NKp46/NCR1 is considered a selective marker for NK cells, although it is also found on a subset of ILCs, where it appears to be without function (see Abstract). Glasner et al. found that overexpression of NCR1 in NK cells increased NK cell immunity (see Abstract). Glasner et al. also teach that NKp46 is involved in Type I and Type II diabetes (pg. 1, para. 2).
With respect to the limitation of an antibody that binds to NCR1 with an affinity corresponding to a KD of about 10-7M to 10-11M, Yossef et al. describe developing monoclonal antibodies that target murine NKp46, NCR1 (see Abstract). Specifically, Yossef et al. disclose of antibody NCR1.15 which demonstrated binding affinity of 1.06E-08 M to NCR1 and only targeted NCR1 in murine NK cells (see pg. 5 and Fig. 1C). Yossef et al. disclose that the NCR1.15 antibody had inhibited development of diabetes, an autoimmune disease (see pg. 2), in the LDSTZ model and in NOD mice (see pg. 11; Figs. 4 and 6).
Lastly, with respect to the limitation that the antibody is covalently attached to the agonist or an antagonist of glucocorticoid receptor, Brandish et al. describe antibody drug conjugates for anti-inflammatory applications (see entire document). Specifically, teach of antibody drug conjugates wherein the antibody is conjugated to an anti-inflammatory therapeutic agent via a phosphate-based linker that is covalently attached to the antibody and the anti-inflammatory therapeutic (see pg. 25, lines 5-31). Brandish et al. further describes that the anti-inflammatory therapeutic agent comprise of glucocorticoid receptor agonists, such as cortisol and dexamethasone (see pg. 29). Brandish et al. found that the linkers of their invention provide greater solubility relative to disulfide linkers, cathepsin B-cleavable linkers, esters and acid-sensitive linkers; enable the release of the payload in its parent or unadulterated form; and, provide superior blood stability relative to esters and disulfides (see pg. 28; Figs. 2 and 4A-6D). Brandish et al. also recites other types of linkers in antibody drug conjugates and indicates that linkers should be sufficiently stable while in circulation to allow delivery of the intact antibody drug conjugate to the target cell but also labile to allow release of the drug moiety from the antibody drug conjugate once inside the target cell (see pg. 27, lines 3-20). Brandish et al. teach that the ADC of their invention can be used to treat conditions such as diabetes, cancer, or inflammatory disease (see pg. 24, lines 4-8).
However, the teachings of Pan, Glasner, Yossef, and Brandish et al. fail to disclose of an ADC comprising a selective glucocorticoid receptor agonist as recited in claim 21. This is remedied by De Bosscher.
De Bosscher teaches of selective glucocorticoid receptor modulators in context of anti-inflammatory strategies (see Abstract). De Bosscher teaches that glucocorticoid receptors range of different functionalities depend on factors that include the tissue type, ligand type, receptor variants, cofactor surroundings, and target gene promoters (see Abstract). De Bosscher teaches that modulating glucocorticoids dissociate the transactivation and transrepression mechanisms (see pg. 98, col. 2). De Bosscher teaches that RU24782 and RU24858 exhibited dissociated characteristics, specifically transactivation activity similar to dexamethasone (DEX) and transrepressive activity on AP similarly to prednisolone (see pg. 98, col. 2). De Bosscher teaches that both DEX and RU24858 induced the expression of anti-inflammatory genes and genes involved in metabolism, thus supporting a potential role for nontraditional GR-dependent gene expression (see pg. 100, col. 1). Additionally, De Bosscher discloses of several species of GR modulators including compound A, LGD5552, ZK 216348, and AL-438 (see Table 1). De Bosscher teaches that AL-438 inhibits inflammation in a rat asthma model while showing a decreased potential to enhance blood glucose (see pg. 100, col. 1); ZK 216348 reduced the severity of croton oil-induced ear inflammation, and failed to induce tyrosine aminotransferase (TAT) and to enhance blood glucose levels (see pg. 100, col. 2); and, LGD5552 provided therapeutic potential from the adjuvant-induced arthritis model that showed a strong repression of serum MCP-1 (see pg. 100, col. 2).
Therefore, it would have been obvious to one of ordinary skill in the art at the time of the present invention to modify the ADC described by Pan et al. to develop the ADC of the present invention. One would be motivated to conjugate an anti-NCR1 antibody to a selective glucocorticoid receptor agonist, such as RU24858, AL-438, and ZK 216348, as De Bosscher has disclosed that these selective GR agonists have provided therapeutic benefit to several conditions in mice models. Specifically, these selective GR agonists have reduced inflammation in several different conditions. Also, as demonstrated by Glasner et al., overexpression of NCR1 in NK cells displayed increased NK cell cytotoxicity which will be beneficial in immunotherapeutics, especially for patients with diabetes as NKp46/NCR1 is involved in the development of Type I and Type II diabetes. This is supported by Yossef et al. who demonstrated that an antibody that targets NCR1 with an affinity between 10-7M to 10-11M (specifically, 1.06E-08 M) inhibited the development of diabetes in mice models. Lastly, by linking the anti-inflammatory agent to the antibody covalently, it allows the ADC to be stable while in circulation while also allowing easy release of the antibody once the ADC reaches the target.
Applicant’s Arguments
Applicant traverses the 103 rejections (see pages 8 and 9 of the Remarks filed on 11/19/2025).
Neither Pan nor Glasner teach an ADC comprising an anti-NCR1 antibody. Glasner teaches that NCR1 is an activating receptor that can eliminate abnormal cells, however, NCR1 is used only to target the ADC to natural killer cells in the claimed invention. Yossef teaches an antibody NCR1.15 and that the NCR1.15 antibody inhibited development of diabetes; however, the present claims are not drawn to an ADC wherein the anti-NCR antibody is the effector of any type of treatment. Rather, the GR agonist or antagonist is the effector, and anti-NCR targets the GR agonist or antagonist to the natural killer cell. Brandish teaches a GR agonist conjugated to an antibody, but fails to teach conjugation to an anti-NCR1 antibody, as is required in the invention as claimed. Thus, the combination of Pan, Glasner, Yossef and Brandish fail to make the claimed invention obvious, and in fact, teach away from the invention by describing methods of exploiting NCR1 activation. Thus, the combination of Pan, Glasner, Yossef and Brandish fail to make the claimed invention obvious. De Bosscher's teaching regarding selective GR modulators fails to cure the deficiencies of this combination. The claimed invention is an antibody drug conjugate wherein the sole function of the antibody is to target natural killer cells so that the targeted GR antagonist/agonist component modulates the glucocorticoid-PD1 pathway and reduces IFN production. Thus, the combination of Pan, Glasner, Yossef, Brandish and De Bosscher fail to make the claimed invention obvious.
Response to Arguments
Applicant's arguments filed 11/19/2025 have been fully considered but they are not persuasive.
As stated in the responses mailed 06/13/2024 and 05/20/2025, Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Examiner agrees that Pan and Glasner do not teach of an ADC comprising an anti-NCR1 antibody, however, Glasner provides motivation for the teaching of Yossef as to why one would want to utilize an anti-NCR1 antibody for an ADC. Additionally, Brandish provides motivation as to why one would want to develop an ADC with a GR agonist. As such, the combination of the teachings provide one of skill in the art ample motivation to develop the ADC of the instant application. Furthermore, in regard to Applicant’s claim that the combination of teachings teach away from the invention by describing methods of exploiting NCR1 activation, Applicant is reminded that a true “teaching away" from a concept must be explicit, not just an otherwise general suggestion. Furthermore, “the prior art' s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). In this case, the art may have described methods of exploiting NCR1 activation with anti-NCR1 antibodies, however, that does not exclude targeting natural killer cells with anti-NCR1 antibodies. Additionally, Brandish provides motivation as to why one would want to develop an ADC with a GR agonist and De Bosscher provides motivation as to why one would want to develop an ADC with selective GR modulators. As such, the combination of the teachings provide one of skill in the art ample motivation to develop the ADC of the instant application.
As such, the 103 rejections are maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674