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 .
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 11/17/22. It is noted, however, that applicant has not filed a certified copy of the 202211439397.5 application as required by 37 CFR 1.55.
Election/Restrictions
Applicant’s election of Group I in the reply filed on 6/22/26 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant has amended claims 11 and 12 to recite a method instead of a use. Newly amended claims 11 and 12 are directed to an invention that is independent or distinct from the inventions originally claimed, and therefore placed in a new Invention III for the following reasons:
Inventions I and III are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case the product as claimed can be used for a materially different process, such as an in vivo assay including affinity purification of a target protein or immunological detection of an antigen.
Inventions II and III are directed to related processes. The related inventions are distinct if: (1) the inventions as claimed are either not capable of use together or can have a materially different design, mode of operation, function, or effect; (2) the inventions do not overlap in scope, i.e., are mutually exclusive; and (3) the inventions as claimed are not obvious variants. See MPEP § 806.05(j). In the instant case, the inventions as claimed have different steps and different intended purposes, with invention II being directed to a method of making and invention III being directed to a method of using. The inventions do not overlap in scope and the claimed steps are mutually exclusive. Furthermore, the inventions as claimed do not encompass overlapping subject matter and there is nothing of record to show them to be obvious variants.
Accordingly, claims 11-12 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Claim Status
The claim amendments filed 6/22/26 are acknowledged. Claims 1-2, 4-6, 9-12 are amended. New claims 13-15 are added.
Claims 1-15 are pending.
Claims 7-8 and 11-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/22/26.
Claims 1-6, 9-10, and 13-15 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statement filed on 4/24/24 has been considered. A signed copy is enclosed.
Applicant is advised that the listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper.” Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they will be considered.
Claim Objections
Claims 1-2 and 10 are objected to because of the following informalities: the term “A-FABP” contains an acronym, abbreviation and/or initialism that should be spelled out upon first occurrence. Appropriate correction is required. Claims 3, 4, 6, 9, and 15 are objected to as being dependent upon claim 1, which has been objected to.
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.
Written Description
Claim 10 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
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 rejected claim is drawn to a pharmaceutical composition comprising a monoclonal antibody or antigen according to claim 1 that neutralizes A-FABP, and one or more other pharmaceutical active ingredients for preventing and/or treating elevated circulating A-FABP or a disease or symptom resulting therefrom. The antibody of claim 1 is adequately described, however, the “one or more other pharmaceutical active ingredients” are not adequately described. The other active ingredients are required to have specific functions including preventing and/or treating elevated circulating A-FABP or a disease or symptom resulting therefrom. The instant specification provides the examples of ischemic stroke, obesity, liver cirrhosis, arteriosclerosis, and diabetes for the diseases that can be prevented and/or treated. The instant specification does not name any embodiments for the other pharmaceutically active ingredients.
When given its broadest reasonable interpretation, claim 10 any protein, peptide, nucleic acid, antibody, antibody fragment, aptamer, small molecule, or any other possible agent that can prevent or treat a wide variety of diseases, the genus for which has not been adequately described, and each of which has a unique etiology and pathology. These agents have no correlation between their structure and function. The claim requires that the other pharmaceutical active ingredient has specific types of activity, but the specification provides no guidance regarding which agents are capable of the required function. Therefore, the specification provides insufficient written description to support the genus 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.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed agents, 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. 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 proteins and peptides, 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. 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).
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 genus of agents encompassed by the instant claims (see e.g. page 661, left column).
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 any given protein 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 prevent 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.
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 agents or a sufficient structure-function correlation to meet the written description requirements.
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.
Enablement
Claim 10 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
1) nature of the invention; 2) the breadth of the claims;
The rejected claim is drawn to a pharmaceutical composition comprising a monoclonal antibody or antigen according to claim 1 that neutralizes A-FABP, and one or more other pharmaceutical active ingredients for preventing and/or treating elevated circulating A-FABP or a disease or symptom resulting therefrom. The other active ingredients are required to have specific functions including preventing and/or treating elevated circulating A-FABP or a disease or symptom resulting therefrom. The instant specification provides the examples of ischemic stroke, obesity, liver cirrhosis, arteriosclerosis, and diabetes for the diseases that can be prevented and/or treated, but the claim encompasses a far broader genus of diseases. The instant specification does not name any embodiments for the other pharmaceutically active ingredients. When given its broadest reasonable interpretation, claim 10 any protein, peptide, nucleic acid, antibody, antibody fragment, aptamer, small molecule, or any other possible agent that can prevent or treat a wide variety of diseases, each of which has a unique etiology and pathology. Thousands of possible agents may be encompassed. The only common feature is that the disease or symptom result from “elevated circulating A-FABP”. Therefore hundreds of diseases and symptoms may be encompassed. Both the genus of other pharmaceutically active agents, and the genus of encompassed diseases and symptoms therefrom, are overly broad. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. The encompassed diseases and symptoms are highly heterogenous at both the molecular and clinical level and the encompassed agents are highly heterogenous at the molecular level.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
The problem of predicting the therapeutic potential of all of the encompassed agents and in turn utilizing predicted activities to ascertain functional aspects of the class members is extremely complex.
3) the state of the prior art; 5) the level of predictability in the art;
Regarding the encompassed proteins and peptides, 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. 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).
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 genus of agents encompassed by the instant claims (see e.g. page 661, left column).
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 any given protein 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 prevent 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.
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).
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples;
The instant specification sets forth Example 4, which evaluates the therapeutic potential of monoclonal antibody 6H2, which has the same CDRs as the antibody in instant claim 1. The 6H2 antibody was administered to mice that were subjected to MCAO surgery for 1 hour, and the experiment indicated that administration of the antibody could reduce infarct volume and alleviate blood-brain barrier disruption caused by ischemia. However, no other agent was identified or administered that “prevents and/or treats elevated circulating A-FABP or a disease or symptom resulting therefrom.” One of skill in the art would first be required to identify which agents fall within the encompassed genera of other agents, and given the heterogeneity of disorders and agents, then would be required to test those agents in hundreds of disorders to determine if preventing and/or treating the disorder was possible. This level of experimentation is undue, and therefore the claimed invention is not enabled.
Due to the large quantity of experimentation necessary to test the administration of each agent encompassed by the claims, the lack of direction/guidance presented in the specification regarding which diseases and/or symptoms could be prevented and/or treated with the agents, the absence of working examples directed to any agent except the 6H2 antibody, the complex nature of the invention, the state of the prior art which establishes the unpredictability of the therapeutic application for the agent, and the breadth of the claims which fail to recite any structural or functional limitations, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
In conclusion, the claimed invention does not provide enablement for the claimed invention. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 5, 10, and 13-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites “the heavy chain variable region CDRs 1, 2, and 3” and “light chain variable region CDRs 1, 2, and 3” without providing the CDR sequences. The claim names a SEQ ID NO: for the heavy and light chains. There are several well established methods to determine CDRs. Using common methods to identify the CDRs produces variable CDR sequences. One of skill in the art would not know which of these embodiments would meet the requirements of the claims. The differences in CDRs may have different affinities that would not be capable of the required neutralizing functions.
Claim 5 recites “an amino acid sequence of the heavy chain variable region” and “an amino acid sequence of the light chain variable region.” It is possible, given the language of the claim which includes "an amino acid sequence ", that any two amino acids in sequence would suffice to meet the limitations of the claims. It is also possible that the claim is intended to require the entire sequence named in the SEQ ID NO. It is unclear which proteins are encompassed by the term “an amino acid sequence” and therefore the claim scope is indefinite.
In claim 10, the phrase “preventing and/or treating” renders the claim indefinite. One of skill in the art cannot both prevent and treat disease at the same time. Therefore the scope of the claims is indefinite.
The term “elevated” in claim 10 is a relative term which renders the claim indefinite. The term “elevated” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 13 and 14 recite the phrase “wherein the humanized antibody comprises human IgG1, IgG2, IgG3, or IgG4” or “wherein the humanized antibody comprises human IgG4.” The instant specification defines “humanized antibody” to refer to “an immunoglobulin including a human framework region and one or more CDR’s from a non-human (usually a mouse or rat) immunoglobulin.” However, the claim recites a requirement for an entirely human IgG. It is impossible to require a “human IgG” and then also require that part of the IgG is not human at the same time. Therefore the claim scope is indefinite.
Allowable Subject Matter
The CDRs, heavy and light chain of the claimed antibody are free of the prior art.
The closest available prior art is as follows:
Hochstrasser et al (WO 2005/029088 A2; filed 9/20/04; published 3/31/05) teaches a method of diagnosis of brain damaged related disorder of possibility thereof in a subject suspected of suffering therefrom, which comprising detecting at least one polypeptide, wherein the polypeptide can be A-FABP (see e.g. Hochstrasser claim 1). The polypeptide can be detected with an antibody to the polypeptide (see e.g. Hochstrasser claim 2). However, Hochstrasser does not teach the same sequences as the instant antibody, and therefore does not read on the instant claims.
Burak et al (Sci Transl Med. 2015 Dec 23;7(319):319ra205. Epub 2015 Dec 23.) teaches development of CA33, CA13, CA15, and CA23 antibodies that were raised against the full length human and mouse aP2/FABP4/A-FABP peptides (see e.g. abstract and page 2, left column). However, Hochstrasser does not teach the same sequences as the instant antibody, and therefore does not read on the instant claims.
Conclusion
No claims are allowed.
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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674
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