DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
The amendments filed 11/18/25 are acknowledged. Claims 1-45, 47-50, 52, 54, 56, 60, 65, 68, 70, 72, 74-75, 77, 79, and 82 are cancelled. Claims 46, 51, 53, 55, 57, 59, 61, 63, 67, 69, 71, 73, and 84 are amended. Claims 46, 51, 53, 55, 57-59, 61-64, 66-67, 69, 71, 73, 76, 78, 80-81, and 83-86 are pending.
Claims 46, 51, 53, 55, 57-59, 61-64, 66-67, 69, 71, 73, 76, 78, 80-81, and 83-86 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statements filed on 11/18/25 and 1/6/26 have been considered. Signed copies are enclosed.
Objections Withdrawn
The objection to the specification for the use of numerous trademarks have been noted in this application on multiple pages is withdrawn in light of Applicant’s amendments thereto.
The objection to claims 51, 53, and 55 because of the following informalities: the claim lacks an appropriate conjunction between the subparts such as “and” or “or” or “and/or” is withdrawn in light of Applicant’s amendments thereto. The objection to claims 47 and 49 is rendered moot by cancellation of the claims.
The objection to claim 49 because of the following informalities: the phrase “according to the number of the EU Index” should be amended to read “according to the numbering of the EU index” is rendered moot by cancellation of the claim.
The objection to claims 57, 69, and 71 are objected to because of the following informalities: the claims contain acronyms and/or abbreviations that should be spelled out upon first occurrence is withdrawn in light of Applicant’s amendments thereto.
The objection to claims 59, 61, and 67 because of the following informalities: the structures are not clearly displayed is withdrawn in light of Applicant’s amendments thereto.
Objections Maintained
Claim Objections
Claim 73 is objected to because of the following informalities: the claim subparts are designated with a period. Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). It is recommended that the claim subparts be designated with parentheses, such as “(a)” or “a)”. Appropriate correction is required.
Applicant has amended the claim to remove the subpart designation punctuation for “I” and “ii”, but did not amend to remove the periods for “a,” “b,” and “c.” Therefore the objection is maintained.
New Objections
Claim Objections
Claim 46 is objected to because of the following informalities: there are two (a) and (b) subpart designations. Appropriate correction is required.
Claim 46 is objected to because of the following informalities: the subpart (a) reciting the heavy and light chain variable regions does not recite a conjunction such as “and” or “or” before subpart (b). Appropriate correction is required.
Claim 51, 53, and 55 are objected to because of the following informalities: the claim subparts are designated with a period. Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). It is recommended that the claim subparts be designated with parentheses, such as “(a)” or “a)”. Appropriate correction is required.
Claim Rejections Withdrawn
The rejection of claims 53, 73, and 84 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of Applicant’s amendments thereto. The rejection of claims 47, 49, 68, and 82 is rendered moot by cancellation of the claims.
Claim Rejections Maintained
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The rejection of claims 69 and 71 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 is maintained. The rejection of claims 46, 51, 53, 55, 57-59, 61-64, 66-67, 76, 78, 80-81, and 83-86 is withdrawn in light of Applicant’s amendments thereto. The rejection of claims 68, 77, 79, and 82 is rendered moot by cancellation of the claims. 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.
The instant claims are drawn to a method of treating an extra domain B of fibronectin-expressing disorder or disease, the method comprising administering an effective amount of a composition of the antibody-drug conjugate comprising an antibody or antigen binding fragment that binds to extra domain B of fibronectin, a linker and a drug, wherein the disease is a cancer selected from the group consisting of non-small cell lung cancer, colon cancer, pancreatic cancer, lymphoma, triple negative breast cancer, and ovarian cancer. The dependent claims recite an antibody or antigen binding fragment comprising three CDRs of SEQ ID NO:21 or 10, or a heavy chain variable region of SEQ ID NO:21 or a light chain variable region of SEQ ID NO:10. There are at least two separate issues regarding written description.
The rejected claims recite administration of two genera of agents defined entirely by function. These agents are encompassed by the terms “anti-Programmed Cell Death Ligand 1 (PDL-1) antagonist” and “anti-Programmed cell death protein 1 (PD1) antagonist”. These terms are not specifically defined, and no structure is provided to correlate with the required function. Further, no criteria are set forth in the specification to clearly define the scope of the encompassed inhibitors, other than to recite their function. The specification only defines the potential targets of the antagonists, without defining the agent structure correlating to these functions.
These agents have no correlation between their structure and function. A sufficiently representative number of species have not been provided. The specification provides no guidance regarding which agents are capable of the required function. Therefore, the specification provides insufficient written description to support the genera encompassed by the claim. 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.)
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.
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 USPQ2datl966.
Regarding the encompassed protein and peptide inhibitors, and the encompassed antibodies, 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), 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 cells (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) 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) 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) 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) 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 and peptides that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), 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 genera encompassed by the instant claims (see e.g. page 661, left column).
Given the teachings of these references that point out the limitations and pitfalls of using sequence to predict functions, and the lack of a representative number of species across the breadth of the genus, one of skill in the art would reasonably conclude that the claims do not meet the written description provision of 35 USC 112(a).
Regarding the encompassed antibodies and fragments thereof, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation 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. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) 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." 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), 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.
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. 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.
The prior art recognizes that the antigen binding by antibodies requires precise orientation of the complementarity determining region (CDR) loops in the variable domain to establish the correct contact surface. For example, Vattekatte, (PeerJ. 2020 Mar 6:8:e8408. doi: 10.7717/peerj.8408. eCollection 2020.) teach that antigen binding in heavy chain only antibodies, (HCAbs) is mediated by only three CDR loops from the single variable domain (VHH) at the N-terminus of each heavy chain, (see abstract). The Vattekatte et al further teach that the amino acid length distribution in different regions of VHH (see Fig. S7) shows diversity in CDR lengths, and that most diversity in CDR3, (see page 7 and 19). However, the prior art also recognizes that a single protein can be bound by a very large and structurally diverse genus of antibodies (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes). For example, Edwards et al. (Mol Biol. 2003 Nov 14;334(1):103-18) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines), and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (see table 2, figure 2).
Lloyd et al. (Protein Eng Des Sel. 2009 Mar;22(3):159-68. Epub 2008 Oct 29.) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, (abstract). The Lloyd et al reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen (page 167, column 1). Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (page 159, column 2).
Goel et al. (J Immunol. 2004 Dec 15;173(12):7358-67) teach that three mAbs that bind to the same short (12-mer) peptide, exhibit diverse V gene usage, indicating their independent germline origin. Said reference further teaches that two of these mAbs recognize the same set of amino acid residues defining the epitope (alternate amino acid residues spread over the entire sequence), however, the relative contribution of each set of residues in the peptide showed significant variation. The reference notes that all of the mAbs do not show any kind of V gene restriction among themselves, implying variable paratope structure, despite that two of these mAbs bind to the peptide through a common set of residues. (See entire reference).
Khan et al. (J Immunol (2014) 192 (11): 5398–5405) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the antibodies possessing entirely different CDR sequences. Said reference teaches that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell response is composed of BCRs having a high degree of structural adaptability. Said reference also teaches that the common epitope(s) also adopt distinct conformations when bound to different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said reference further teaches “It has been shown that both the framework region and the CDRs have a considerable amount of inherent conformational plasticity...Therefore, it is not surprising that distinct germline Abs recognize the same epitope by rearranging the CDR conformations. This may well have implications of Ag specificity beyond the naive BCR repertoire, because Kaji et al... .have shown in a recent report that the B cell memory can contain both germline-encoded and somatically mutated BCRs.” (See entire reference).
Poosarla et al. (Biotechnol Bioeng. 2017 June ; 114(6): 1331–1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Rabia, et al. (Biochem Eng J. 2018 Sep 15:137:365-374. Epub 2018 Jun 5) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al. report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Rabia et al. thus teach that affinity and specificity are not necessarily correlated and that an increase in affinity does not indicate an increase in specificity (Fig. 3; p. 368, col. 1, section 3,1st full paragraph to col. 2, 2nd full paragraph).
Therefore, 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 small molecule inhibitors 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), 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 a given 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), 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 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), 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) 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) 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.
Applicant is reminded that generally, 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 (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). 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 Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). 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).
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the 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 Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and 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. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Applicant’s Arguments
Applicant argues:
1. Claim 46 has been amended to recite specific CDRs, and therefore the antibodies and binding fragments thereof are fully described.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. The claims have been amended to recite specific CDRs, and therefore the antibodies and binding fragments thereof are adequately described. The rejection has been amended to reflect current claim amendments. However, the rejected claims recite genera of agents that are defined entirely by their functions, without providing a corresponding structure. Furthermore, a representative number of species have not been presented. Therefore, the rejection of claims 69 and 71 is maintained.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The rejection of claim(s) 46, 58, 62-64, 73, 76, 78, and 81 under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Casi et al (WO 2015/114166 A2; filed 2/3/15, published 8/6/15) is maintained. The rejection of claims 47, 68, 77 and 79 is rendered moot by cancellation of the claims.
The instant claims are directed to a method of treating an extra domain B of fibronectin-expressing disorder or disease, comprising administering a composition comprising an antibody drug conjugate comprising an antibody or antigen binding fragment that binds to an extra domain B of fibronectin, a linker and a drug. The disorder or disease is a cancer selected from the group consisting of non-small cell lung cancer, colon cancer, pancreatic cancer, lymphoma, triple negative breast cancer, and ovarian cancer. The antibody can comprise the CDRs of SEQ ID NO:21 and CDRs of SEQ ID NO:10. The claims reciting CDRs have been interpreted to only require the CDRs, and not the entire sequence of the antibody variable regions of SEQ ID NO:21 and SEQ ID NO:10. The drug can be an auristatin, and the linker can be a cleavable linker.
Casi teaches a targeted therapeutic agent comprising a compound having an antibody and a cytotoxic drug moiety linked by a linker (see e.g. abstract). The conjugate can be produced comprising a step of forming a cleavable disulfide bond through the sulfur of the thiol group to bond the drug to the linker moiety in the conjugates of the invention (see e.g. page 26, 34). The formula is shown on page 3, as B-L-D, where B is a binding moiety, D is a cytotoxic drug, and L is a linker group (see e.g. page 3). One of the antibodies can be the anti-EDB-L19 which comprises the sequences of the instant CDRs in the reference’s SEQ ID NO:1 and SEQ ID NO:2 (see e.g. page 17, including antibody sequence with CDRs highlighted below, for the VH, the sequences for the CDRs of claim 38 are indicated by lines below the sequence, claim 39 is indicated by the lines above the sequence). The drug can be an auristatin (see e.g. paragraph spanning page 22-23). The linker can be a cleavable linker (see e.g. page 4, “L is a linker group that undergoes cleave in vivo for releasing said drug moiety…”; see also pages 18-19). The compound can be used to treat cancer (see e.g. page 4 and page 28). The composition can be administered with another agent, such as an immunomodulator (see e.g. page 32). Applicant has not defined the term “immunooncology agent” or “immune checkpoint inhibitor”. Therefore, the instant claims will be interpreted to read on any agent that can modulate the immune system and treat cancer, such as the second agent of Casi.
Sequences from page 17, with CDRs highlighted:
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Applicant’s Arguments
Applicant argues:
1. The claims recite that the disorder or disease is a cancer selected from a group of four specific cancer types. Casi does not disclose this specific group of four cancer types, and Casi does not provide any guidance as to why this specific set of cancers would be grouped together. Casi provides at least 30 different types of cancer resulting in a large number of combinations of possible cancers, even if one were to concentrate on combinations of four cancer types from those named. Without specific guidance from Casi regarding the grouping of cancers, it is unclear why a person of skill in the art would select specific cancers to group them together. The cancer types are not arranged or combined in the same way as the claim.
2. The reference would not enable a skilled artisan to practice the method without undue experimentation because Casi does not contain any data regarding the use of an L19-based antibody for the treatment of cancer. Therefore, undue experimentation would be needed to develop, analyze and confirm the treatment capabilities of the instant antibody.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. Anticipation does not require that all species are named in a reference, but merely that at least one species of a claimed genus is named (see MPEP 2131.02). A single species will anticipate a claim to a genus (see MPEP 2131.02). Therefore, naming of any species of cancer listed in the instant claims would anticipate the genus. Casi clearly names non-small cell lung cancer, pancreatic, and ovarian cancer (see e.g. page 28). Because these species are specifically named, and Casi teaches treatment of these cancers with the instant conjugate, the claims are anticipated. Furthermore, MPEP 2131.02 states that when a species is clearly named, the species claim is anticipated no matter how many other species are additionally named. See Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990).
2. A reference contains an “enabling disclosure” if the public was in possession of the claimed invention before the date of invention. “Such possession is effected if one of ordinary skill in the art could have combined the publication’s description of the invention with his [or her] own knowledge to make the claimed invention.” In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed. Cir. 1985). The Examiner asserts that one of ordinary skill in the art would have been able to select the fully described antibody conjugate including an antibody specifically described by sequences containing the exact same CDR sequences as the instant invention, within a drug conjugate having the same elements as the instant claims, as shown in the formula on Casi page 3. The question is then whether one of skill in the art would have been able to administer the selected compound to a person with cancer. The administration step itself is well within the skill of an ordinary medical practitioner. Regarding whether one would have selected a person with cancer for administration, the reference teaches "One particular disease that is applicable to treatment by the present invention is neoplastic disease such as cancer that can be treated via the targeted destruction of the established tumour vasculature. Non-limiting examples of cancers that may be treated include benign and malignant tumours; leukemia and lymphoid malignancies, including breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, thyroid, pancreatic, prostate or bladder cancer" (see Casi page 28). Taken together, one of skill in the art can reasonably conclude that administration of the recited conjugate would treat the types of cancer presented in the reference. The reference teaches the specific conjugate including antibody sequences, and identifies a use for the conjugate to treat a group of specific conditions or disorders, including several of the same types of cancer as shown in the instant claims.
Applicant appears to argue a requirement for Casi to demonstrate efficacy or provide dosage to prove that the described method is enabled. However, as found by the Federal Circuit in Impax Laboratories Inc. v. Aventis Pharmaceuticals Inc., 81 USPQ2d 1001 (Fed. Cir. 2006), “proof of efficacy is not required for a prior art reference to be enabling under section 102. Id.; see also Novo Nordisk Pharms., Inc. v. Bio-Tech. Gen. Corp., 424 F.3d 1347, 1355 [76 USPQ2d 1811] (Fed. Cir. 2005) (“The standard for enablement of a prior art reference for purposes of anticipation under section 102 differs from the enablement standard under 35 U.S.C. § 112. While section 112 ‘provides that the specification must enable one skilled in the art to “use” the invention,’ … ‘section 102 makes no such requirement as to an anticipatory disclosure”. The Court has specifically stated that “anticipation does not require actual performance of suggestions in a disclosure. Rather, anticipation only requires that those suggestions be enabled to one of skill in the art.” See Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1378 [58 USPQ2d 1508] (Fed. Cir. 2001) (holding that prior art that suggested a drug was ineffective nevertheless anticipated a patent on that drug); Celeritas Techs. v. Rockwell Int'l Corp., 150 F.3d 1354, 1361 [47 USPQ2d 1516] (Fed. Cir. 1998) (“A reference is no less anticipatory if, after disclosing the invention, the reference then disparages it. Thus, the question whether a reference ‘teaches away’ from the invention is inapplicable to an anticipation analysis.”).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The rejection of claim(s) 46, 58, 62-64, 73, 76, 78, 81, and 85-86 under 35 U.S.C. 103 as being unpatentable over Casi et al (WO 2015/114166 A2; filed 2/3/15, published 8/6/15) is maintained. The rejection of claims 47, 68, 77 and 79 is rendered moot by cancellation of the claims.
The instant claims are directed to a method of treating an extra domain B of fibronectin-expressing disorder or disease, comprising administering a composition comprising an antibody drug conjugate comprising an antibody or antigen binding fragment that binds to an extra domain B of fibronectin, a linker and a drug. The disorder or disease is a cancer selected from the group consisting of non-small cell lung cancer, colon cancer, pancreatic cancer, lymphoma, triple negative breast cancer, and ovarian cancer. The antibody can comprise the CDRs of SEQ ID NO:21 and CDRs of SEQ ID NO:10. The claims reciting CDRs have been interpreted to only require the CDRs, and not the entire sequence of the antibody variable regions of SEQ ID NO:21 and SEQ ID NO:10. The drug can be an auristatin, and the linker can be a cleavable linker.
Casi teaches a targeted therapeutic agent comprising a compound having an antibody and a cytotoxic drug moiety linked by a linker (see e.g. abstract). The conjugate can be produced comprising a step of forming a cleavable disulfide bond through the sulfur of the thiol group to bond the drug to the linker moiety in the conjugates of the invention (see e.g. page 26, 34). The formula is shown on page 3, as B-L-D, where B is a binding moiety, D is a cytotoxic drug, and L is a linker group (see e.g. page 3). One of the antibodies can be the anti-EDB-L19 which comprises the sequences of the instant CDRs in the reference’s SEQ ID NO:1 and SEQ ID NO:2 (see e.g. page 17, including antibody sequence with CDRs highlighted below, for the VH, the sequences for the CDRs of claim 38 are indicated by lines below the sequence, claim 39 is indicated by the lines above the sequence). The drug can be an auristatin (see e.g. paragraph spanning page 22-23). The linker can be a cleavable linker (see e.g. page 4, “L is a linker group that undergoes cleave in vivo for releasing said drug moiety…”; see also pages 18-19). The compound can be used to treat cancer (see e.g. page 4 and page 28). The composition can be administered with another agent, such as an immunomodulator (see e.g. page 32). Applicant has not defined the term “immunooncology agent” or “immune checkpoint inhibitor”. Therefore, the instant claims will be interpreted to read on any agent that can modulate the immune system and treat cancer, such as the second agent of Casi.
Sequences from page 17, with CDRs highlighted:
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Casi does not teach a specific drug-to-antibody-ratio.
It would have been obvious to one of ordinary skill in the art to optimize the drug to antibody ratio since “it is the normal desire of scientists or artisans to improve upon what is already generally known”. The MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller. 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson. 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc, v. Biocraft Laboratories Inc.. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert, denied, 493 U.S. 975 (1989); In re Kulling. 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler. 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Applicant’s Arguments
Applicant argues:
1. The claims recite that the disorder or disease is a cancer selected from a group of four specific cancer types. Casi does not disclose this specific group of four cancer types, and Casi does not provide any guidance as to why this specific set of cancers would be grouped together. Casi provides at least 30 different types of cancer resulting in a large number of combinations of possible cancers, even if one were to concentrate on combinations of four cancer types from those named. Without specific guidance from Casi regarding the grouping of cancers, it is unclear why a person of skill in the art would select specific cancers to group them together. The cancer types are not arranged or combined in the same way as the claim.
2. Casi fails the KSR test because the reference does not provide a reasonable expectation of success. In particular, Casi does not disclose any actual data regarding use of an L19-based antibody for the treatment of cancer. Casi only teaches administration of a different antibody in other types of cancer. There is no actual evidence that EDB-FN targeting antibody would be successful in treating a cancer listed in the instant claims.
3. Applicants submit that a skill artisan would not have predicted the surprising and unexpected results demonstrated by the present application for the treatment of the recited cancer types using the claimed ADCs.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. Anticipation does not require that all species are named in a reference, but merely that at least one species of a claimed genus is named (see MPEP 2131.02). A single species will anticipate a claim to a genus (see MPEP 2131.02). Therefore, naming of any species of cancer listed in the instant claims would anticipate the genus. Casi clearly names non-small cell lung cancer, pancreatic, and ovarian cancer (see e.g. page 28). Because these species are specifically named, and Casi teaches treatment of these cancers with the instant conjugate, the claims are anticipated. Furthermore, MPEP 2131.02 states that when a species is clearly named, the species claim is anticipated no matter how many other species are additionally named. See Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990).
2. MPEP 2143.02 states that “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’").” The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016).
The Examiner asserts that one of ordinary skill in the art would have been able to select the fully described antibody conjugate including an antibody specifically described by sequences containing the exact same CDR sequences as the instant claims, within a drug conjugate having the same elements as the instant claims, as shown in the formula on Casi page 3. The question is then whether one of skill in the art would have been able to administer the selected compound to a person with cancer. The administration step itself is well within the skill of an ordinary medical practitioner. Regarding whether one would have selected a person with cancer for administration, the reference teaches "One particular disease that is applicable to treatment by the present invention is neoplastic disease such as cancer that can be treated via the targeted destruction of the established tumour vasculature. Non-limiting examples of cancers that may be treated include benign and malignant tumours; leukemia and lymphoid malignancies, including breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, thyroid, pancreatic, prostate or bladder cancer" (see Casi page 28). Taken together, one of skill in the art can reasonably conclude that administration of the recited conjugate would treat the types of cancer presented in the reference. The reference teaches the specific conjugate including antibody sequences, and identifies a use for the conjugate to treat a group of specific conditions or disorders, including several of the same types of cancer as shown in the instant claims. MPEP 2144.05 also states that the differences in chemical parameters of the composition will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such limitations are critical. Applicant has not demonstrated criticality for specific drug to antibody ratios, and optimization to achieve maximal functionality of the composition would be inherently desirable to a medical practitioner as one of skill in the art.
3. As stated above, treatment of cancer with the conjugate of the instant invention is anticipated by Casi. Therefore, the effect of treating those types of cancer is expected based on the prior art. As stated in MPEP 716.02(c), "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). Furthermore, arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); see MPEP 2145.
The rejection of claim(s) 46, 53, 57-59, 61-64, 66-67, 73, 76, 78, 81, and 83-86 under 35 U.S.C. 103 as being unpatentable over Casi et al (WO 2015/114166 A2; filed 2/3/15, published 8/6/15) in view of Ma et al (US 2017/0151341 A1; filed 11/21/16; priority 11/30/15; published 6/1/17) is maintained. The rejection of claims 47, 49, 68, 77 and 79 is rendered moot by cancellation of the claims.
The applied Ma reference has a common inventor and applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
The instant claims are directed to a method of treating an extra domain B of fibronectin-expressing disorder or disease, comprising administering a composition comprising an antibody drug conjugate comprising an antibody or antigen binding fragment that binds to an extra domain B of fibronectin, a linker and a drug. The disorder or disease is a cancer selected from the group consisting of non-small cell lung cancer, colon cancer, pancreatic cancer, lymphoma, triple negative breast cancer, and ovarian cancer. The antibody can comprise the CDRs of SEQ ID NO:21 and CDRs of SEQ ID NO:10. The claims reciting CDRs have been interpreted to only require the CDRs, and not the entire sequence of the antibody variable regions of SEQ ID NO:21 and SEQ ID NO:10. The drug can be an auristatin, and the linker can be a cleavable linker.
Casi teaches a targeted therapeutic agent comprising a compound having an antibody and a cytotoxic drug moiety linked by a linker (see e.g. abstract). The conjugate can be produced comprising a step of forming a cleavable disulfide bond through the sulfur of the thiol group to bond the drug to the linker moiety in the conjugates of the invention (see e.g. page 26, 34). The formula is shown on page 3, as B-L-D, where B is a binding moiety, D is a cytotoxic drug, and L is a linker group (see e.g. page 3). One of the antibodies can be the anti-EDB-L19 which comprises the sequences of the instant CDRs in the reference’s SEQ ID NO:1 and SEQ ID NO:2 (see e.g. page 17, including antibody sequence with CDRs highlighted below, for the VH, the sequences for the CDRs of claim 38 are indicated by lines below the sequence, claim 39 is indicated by the lines above the sequence). The drug can be an auristatin (see e.g. paragraph spanning page 22-23). The linker can be a cleavable linker (see e.g. page 4, “L is a linker group that undergoes cleave in vivo for releasing said drug moiety…”; see also pages 18-19). The compound can be used to treat cancer (see e.g. page 4 and page 28). The composition can be administered with another agent, such as an immunomodulator (see e.g. page 32). Applicant has not defined the term “immunooncology agent” or “immune checkpoint inhibitor”. Therefore, the instant claims will be interpreted to read on any agent that can modulate the immune system and treat cancer, such as the second agent of Casi.
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Casi does not teach a specific drug-to-antibody-ratio. Casi does not teach that the antibody can comprise a lysine to arginine mutation of K222R. Casi does not teach that the antibody can comprise a cysteine at position 290, and/or cysteine at position 183. Casi does not teach that the linker can be vc, and the drug can be 0101. Casi does not teach that the antibody can comprise a glutamine tag.
Ma teaches site specific HER2 antibody drug conjugates and methods for preparing the conjugates. The antibody can comprise a K222R substitution, which resulted in more homogenous antibody and payload conjugate, and which can decrease interchain crosslinking with the glutamine tag on the C terminus of the antibody light chain (see e.g. paragraph [0208]). The antibody can comprise mutants comprising K183C+K290C (see e.g. paragraphs [0209]-[0210]). The 290 site is particularly useful for conjugation of payloads that include vc-0101 (see e.g. paragraph [0227], [0286], [0380], Table 9). Ma teaches that the drug-to-antibody ratio (DAR) or drug loading indicates the number of drug (D) molecules that are conjugated per antibody (see e.g. paragraph [0100]). The DAR can be 1-4 (see e.g. paragraph [0100]).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to generate an antibody with the K222R, K183C, and K290C mutations, with a DAR of 1-4, and include a vc-0101 payload because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The modification of antibodies to produce site-specific conjugation, and delivery of a known payload that can be conjugated to these sites, would be a known variation based on the teachings of Ma. One of skill in the art could employ conventional protein modification techniques to produce the mutations (see e.g. paragraph [0072]), and the conjugation to the vc-0101 would also be possible with routine conjugation chemistry (see e.g. paragraph [0133]). Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Applicant’s Arguments
Applicant argues:
1. The claims recite that the disorder or disease is a cancer selected from a group of four specific cancer types. Casi does not disclose this specific group of four cancer types, and Casi does not provide any guidance as to why this specific set of cancers would be grouped together. Casi provides at least 30 different types of cancer resulting in a large number of combinations of possible cancers, even if one were to concentrate on combinations of four cancer types from those named. Without specific guidance from Casi regarding the grouping of cancers, it is unclear why a person of skill in the art would select specific cancers to group them together. The cancer types are not arranged or combined in the same way as the claim.
2. Casi fails the KSR test because the reference does not provide a reasonable expectation of success. In particular, Casi does not disclose any actual data regarding use of an L19-based antibody for the treatment of cancer. Casi only teaches administration of a different antibody in other types of cancer. There is no actual evidence that EDB-FN targeting antibody would be successful in treating a cancer listed in the instant claims.
3. Applicants submit that a skill artisan would not have predicted the surprising and unexpected results demonstrated by the present application for the treatment of the recited cancer types using the claimed ADCs.
4. Ma does not discuss anti-EDB-FN antibodies, and does not provide evidence that anti-EDB-FN antibodies or antigen binding fragments would treat cancer. The ADC used in Ma is distinct from the anti-EDB-FN antibodies of the instant claims. Because the targets of Casi and Ma are distinct, there is no reasonable expectation of success in practicing the methods of the instant claims.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. Anticipation does not require that all species are named in a reference, but merely that at least one species of a claimed genus is named (see MPEP 2131.02). A single species will anticipate a claim to a genus (see MPEP 2131.02). Therefore, naming of any species of cancer listed in the instant claims would anticipate the genus. Casi clearly names non-small cell lung cancer, pancreatic, and ovarian cancer (see e.g. page 28). Because these species are specifically named, and Casi teaches treatment of these cancers with the instant conjugate, the claims are anticipated. Furthermore, MPEP 2131.02 states that when a species is clearly named, the species claim is anticipated no matter how many other species are additionally named. See Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990).
2. MPEP 2143.02 states that “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’").” The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016).
The Examiner asserts that one of ordinary skill in the art would have been able to select the fully described antibody conjugate including an antibody specifically described by sequences containing the exact same CDR sequences as the instant claims, within a drug conjugate having the same elements as the instant claims, as shown in the formula on Casi page 3. The question is then whether one of skill in the art would have been able to administer the selected compound to a person with cancer. The administration step itself is well within the skill of an ordinary medical practitioner. Regarding whether one would have selected a person with cancer for administration, the reference teaches "One particular disease that is applicable to treatment by the present invention is neoplastic disease such as cancer that can be treated via the targeted destruction of the established tumour vasculature. Non-limiting examples of cancers that may be treated include benign and malignant tumours; leukemia and lymphoid malignancies, including breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, thyroid, pancreatic, prostate or bladder cancer" (see Casi page 28). Taken together, one of skill in the art can reasonably conclude that administration of the recited conjugate would treat the types of cancer presented in the reference. The reference teaches the specific conjugate including antibody sequences, and identifies a use for the conjugate to treat a group of specific conditions or disorders, including several of the same types of cancer as shown in the instant claims. MPEP 2144.05 also states that the differences in chemical parameters of the composition will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such limitations are critical. Applicant has not demonstrated criticality for specific drug to antibody ratios, and optimization to achieve maximal functionality of the composition would be inherently desirable to a medical practitioner as one of skill in the art.
3. As stated above, treatment of cancer with the conjugate of the instant invention is anticipated by Casi. Therefore, the effect of treating those types of cancer is expected based on the prior art. As stated in MPEP 716.02(c), "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). Furthermore, arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); see MPEP 2145.
4. Applicant is arguing features of each reference separately without considering the teachings combined as a whole. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). See MPEP 2145. Furthermore, the rejection sets forth a specific reason for applying the teachings of Ma as a known variation in the art, because the substitutions resulted in more homogenous antibody and payload conjugate, and which can decrease interchain crosslinking with the glutamine tag on the C terminus of the antibody light chain (see e.g. paragraph [0208]), and the sites are particularly useful for conjugation of payloads that include vc-0101 (see e.g. paragraph [0227], [0286], [0380], Table 9). Therefore, one of skill in the art would have been motivated to combine the teachings of the two references.
The rejection of claim(s) 46, 58, 62-64, 73, 76, 78, 81, and 85-86 under 35 U.S.C. 103 as being unpatentable over Casi et al (WO 2015/114166 A2; filed 2/3/15, published 8/6/15) in view of Schwager et al (J Invest Dermatol. 2013 Mar;133(3):751-758. doi: 10.1038/jid.2012.376. Epub 2012 Oct 25) is maintained. The rejection of claims 47, 68, 77 and 79 is rendered moot by cancellation of the claims.
The instant claims are directed to a method of treating an extra domain B of fibronectin-expressing disorder or disease, comprising administering a composition comprising an antibody drug conjugate comprising an antibody or antigen binding fragment that binds to an extra domain B of fibronectin, a linker and a drug. The disorder or disease is a cancer selected from the group consisting of non-small cell lung cancer, colon cancer, pancreatic cancer, lymphoma, triple negative breast cancer, and ovarian cancer. The antibody can comprise the CDRs of SEQ ID NO:21 and CDRs of SEQ ID NO:10. The claims reciting CDRs have been interpreted to only require the CDRs, and not the entire sequence of the antibody variable regions of SEQ ID NO:21 and SEQ ID NO:10. The drug can be an auristatin, and the linker can be a cleavable linker.
Casi teaches a targeted therapeutic agent comprising a compound having an antibody and a cytotoxic drug moiety linked by a linker (see e.g. abstract). The conjugate can be produced comprising a step of forming a cleavable disulfide bond through the sulfur of the thiol group to bond the drug to the linker moiety in the conjugates of the invention (see e.g. page 26, 34). The formula is shown on page 3, as B-L-D, where B is a binding moiety, D is a cytotoxic drug, and L is a linker group (see e.g. page 3). One of the antibodies can be the anti-EDB-L19 which comprises the sequences of the instant CDRs in the reference’s SEQ ID NO:1 and SEQ ID NO:2 (see e.g. page 17, including antibody sequence with CDRs highlighted below, for the VH, the sequences for the CDRs of claim 38 are indicated by lines below the sequence, claim 39 is indicated by the lines above the sequence). The drug can be an auristatin (see e.g. paragraph spanning page 22-23). The linker can be a cleavable linker (see e.g. page 4, “L is a linker group that undergoes cleave in vivo for releasing said drug moiety…”; see also pages 18-19). The compound can be used to treat cancer (see e.g. page 4 and page 28). The composition can be administered with another agent, such as an immunomodulator (see e.g. page 32). Applicant has not defined the term “immunooncology agent” or “immune checkpoint inhibitor”. Therefore, the instant claims will be interpreted to read on any agent that can modulate the immune system and treat cancer, such as the second agent of Casi.
Sequences from page 17, with CDRs highlighted:
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Casi does not teach a specific drug-to-antibody-ratio. Casi does not teach combination with an anti-PD1 antagonist.
Schwager teaches administration of the immunocytokine L19-IL2 to treat cancer (see e.g. abstract). The L19 monoclonal antibody binds to extra domain B of fibronectin (EDB) (see e.g. page 751, right column). The combination of the L19-IL2 with an agent that blocks PD-1 resulted in increased survival for mice bearing CT26 colon cancer cell line (see e.g. 754, left column).
It would have been obvious to one of ordinary skill in the art to optimize the drug to antibody ratio since “it is the normal desire of scientists or artisans to improve upon what is already generally known”. The MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller. 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson. 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc, v. Biocraft Laboratories Inc.. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert, denied, 493 U.S. 975 (1989); In re Kulling. 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler. 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the method of Casi to combine the anti-EDB antibody conjugate with anti-PD1 agents as described in Schwager because the combination of anti-EDB antibodies and anti-PD1 agents when combined show a reduction in tumor growth and increased survival. It would be expected, absent evidence to the contrary, that combined administration of the compound of Casi with anti-PD1 agents, would produce similar decrease in tumor growth and increase in lifespan, given that the compounds are targeting the same molecules as in Schwager. The advantage of improved therapeutic activity provides the motivation to make the aforementioned modification of the antibody of Casi, based on the teachings of Schwager, with a reasonable expectation of success.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering an anti-EDB agent in combination with an anti-PD1 agent as taught in Casi and Schwager, one would achieve a method for treating cancer.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Applicant’s Arguments
Applicant argues:
1. The claims recite that the disorder or disease is a cancer selected from a group of four specific cancer types. Casi does not disclose this specific group of four cancer types, and Casi does not provide any guidance as to why this specific set of cancers would be grouped together. Casi provides at least 30 different types of cancer resulting in a large number of combinations of possible cancers, even if one were to concentrate on combinations of four cancer types from those named. Without specific guidance from Casi regarding the grouping of cancers, it is unclear why a person of skill in the art would select specific cancers to group them together. The cancer types are not arranged or combined in the same way as the claim.
2. Casi fails the KSR test because the reference does not provide a reasonable expectation of success. In particular, Casi does not disclose any actual data regarding use of an L19-based antibody for the treatment of cancer. Casi only teaches administration of a different antibody in other types of cancer. There is no actual evidence that EDB-FN targeting antibody would be successful in treating a cancer listed in the instant claims.
3. Applicants submit that a skill artisan would not have predicted the surprising and unexpected results demonstrated by the present application for the treatment of the recited cancer types using the claimed ADCs.
4. Schwager does not discuss anti-EDB-FN antibodies, and does not provide evidence that anti-EDB-FN antibodies or antigen binding fragments would treat cancer. The ADC used in Schwager is distinct from the anti-EDB-FN antibodies of the instant claims. Because the targets of Casi and Schwager are distinct, there is no reasonable expectation of success in practicing the methods of the instant claims.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. Anticipation does not require that all species are named in a reference, but merely that at least one species of a claimed genus is named (see MPEP 2131.02). A single species will anticipate a claim to a genus (see MPEP 2131.02). Therefore, naming of any species of cancer listed in the instant claims would anticipate the genus. Casi clearly names non-small cell lung cancer, pancreatic, and ovarian cancer (see e.g. page 28). Because these species are specifically named, and Casi teaches treatment of these cancers with the instant conjugate, the claims are anticipated. Furthermore, MPEP 2131.02 states that when a species is clearly named, the species claim is anticipated no matter how many other species are additionally named. See Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter. 1990).
2. MPEP 2143.02 states that “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’").” The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016).
The Examiner asserts that one of ordinary skill in the art would have been able to select the fully described antibody conjugate including an antibody specifically described by sequences containing the exact same CDR sequences as the instant claims, within a drug conjugate having the same elements as the instant claims, as shown in the formula on Casi page 3. The question is then whether one of skill in the art would have been able to administer the selected compound to a person with cancer. The administration step itself is well within the skill of an ordinary medical practitioner. Regarding whether one would have selected a person with cancer for administration, the reference teaches "One particular disease that is applicable to treatment by the present invention is neoplastic disease such as cancer that can be treated via the targeted destruction of the established tumour vasculature. Non-limiting examples of cancers that may be treated include benign and malignant tumours; leukemia and lymphoid malignancies, including breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, thyroid, pancreatic, prostate or bladder cancer" (see Casi page 28). Taken together, one of skill in the art can reasonably conclude that administration of the recited conjugate would treat the types of cancer presented in the reference. The reference teaches the specific conjugate including antibody sequences, and identifies a use for the conjugate to treat a group of specific conditions or disorders, including several of the same types of cancer as shown in the instant claims. MPEP 2144.05 also states that the differences in chemical parameters of the composition will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such limitations are critical. Applicant has not demonstrated criticality for specific drug to antibody ratios, and optimization to achieve maximal functionality of the composition would be inherently desirable to a medical practitioner as one of skill in the art.
3. As stated above, treatment of cancer with the conjugate of the instant invention is anticipated by Casi. Therefore, the effect of treating those types of cancer is expected based on the prior art. As stated in MPEP 716.02(c), "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). Furthermore, arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); see MPEP 2145.
4. Applicant is arguing features of each reference separately without considering the teachings combined as a whole. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). See MPEP 2145. Furthermore, the rejection sets forth a specific reason for applying the teachings of Schwager as a known variation in the art, because the combination of anti-EDB antibodies and anti-PD1 agents when combined show a reduction in tumor growth and increased survival. It would be expected, absent evidence to the contrary, that combined administration of the compound of Casi with anti-PD1 agents, would produce similar decrease in tumor growth and increase in lifespan, given that the compounds are targeting the same molecules as in Schwager. The advantage of improved therapeutic activity provides the motivation to make the aforementioned modification of the antibody of Casi, based on the teachings of Schwager, with a reasonable expectation of success. Therefore, one of skill in the art would have been motivated to combine the teachings of the two references.
New Claim Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 46, 51, 53, 55, 57-59, 61-64, 66-67, 69, 71, 76, 78, 80-81, and 83-86 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 46 recites two references (i.e. “Kabat” and “Chothia”). It is unclear if every sequence named must meet the limitations, or if the reference limitations only apply to the sequences immediately preceding the clause naming the references.
Claim 46 recites two references (i.e. “Kabat” and “Chothia”). Where possible, claims are to be complete in themselves. Incorporation by reference to a specific reference “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)". See MPEP2173.05(s).” The limitations of the claim are indefinite based on requiring an outside reference for specific limitations.
Claims depending from the rejected claims do not remedy the deficiency and therefore are also rejected.
Conclusion
No claim is 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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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674
/BRIAN GANGLE/Primary Examiner, Art Unit 1645