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 and arguments filed 8/14/25 are acknowledged. Claims 1-65, 67, 70-74, 76, are cancelled. New claims 85-91 are added. Claims 66, 68-69, 75, and 77-91 are pending.
Claims 77-84 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claim 68 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/7/24.
Claims 66, 69, 75, and 85-91 are currently under consideration for patentability under 37 CFR 1.104.
Withdrawn Objections
The objection to the abstract of the disclosure because the abstract contains the term “ROR2”, which is an acronym and/or abbreviation, and should be spelled out upon first occurrence is withdrawn in light of Applicant’s amendments thereto.
The objection to the disclosure because of the following informalities: on page 13, under “Brief Description of the Figures” the first paragraph lists “Figures 1A-1C” but should be amended to “Figures 1A-1D” is withdrawn in light of Applicant’s amendments thereto.
The objection to claim 66 is objected to because of the following informalities: the phrase “A method of treating osteoarthritis, cartilage loss, osteoarthritis associated pain, promoting cartilage repair and/or preventing cartilage degradation” should be amended to include appropriate punctuation, such as: “A method of treating osteoarthritis, cartilage loss, and/or osteoarthritis associated pain;[[,]] promoting cartilage repair; and/or preventing cartilage degradation;” is withdrawn in light of Applicant’s amendments thereto.
The objection to claim 75 because of the following informalities: the phrase “an ROR2 protein” should be amended to read “[[an]] a ROR2 protein” is withdrawn in light of Applicant’s amendments thereto. The objection to claim 67 is rendered moot by cancellation of the claims.
The objection to claim 69 is objected to because of the following informalities: the phrase “is formulated as a pharmaceutical composition” should be amended to read “is formulated [[as]] in a pharmaceutical composition” is withdrawn in light of Applicant’s amendments thereto.
The objection to claim 75 because of the following informalities: the phrase “the membrane anchor is connected to extracellular domain” should be amended to read “the membrane anchor is connected to the extracellular domain” is withdrawn in light of Applicant’s amendments thereto.
Withdrawn Claim Rejections
The rejection of claim 75 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 objection to claim 67 is rendered moot by cancellation of the claims.
The rejection of claim 76 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is rendered moot by cancellation of the claims.
The rejection of claim(s) 66-67, 69, and 75-76 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Maeda, et al (Nat Med. 2012 Feb 19;18(3):405-12) as evidenced by Pierce™ High-Capacity Endotoxin Removal Resin (Revision A,0 published 10/17/15; downloaded from https://assets.thermofisher.com/TFS-Assets/LSG/manuals/MAN0016351_2162373_PierceHighCapacityEndotoxRemovalResin_UG.pdf on 1/23/25) is withdrawn in light of Applicant’s amendments thereto. Specifically Maeda does not teach a ROR2 inhibitor having at least 95% sequence identity to instant SEQ ID NO:10, and therefore does not anticipate the amended claims. The rejection of claims 67 and 76 is rendered moot by cancellation of the claims.
Maintained Claim Rejections
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
The rejection of claims 66, 69, 75, and 85-91 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 withdrawn in light of Applicant’s amendments thereto is maintained. The rejection has been updated to reflect current claim amendments. The rejection of claims 67 and 76 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 directed to a method of treating osteoarthritis, cartilage loss, osteoarthritis associated pain, promoting cartilage repair and/or preventing cartilage degradation comprising administering to a subject in need thereof a ROR2 inhibitor, wherein the ROR2 inhibitor comprises a fragment of an ROR2 extracellular domain polypeptide of up to 400 amino acids in length and has at least 95% identity to the corresponding amino acids of SEQ ID NO:10. It is noted that the phrase “at least 95% identity to the corresponding amino acids of” renders the claim indefinite (see rejection under 35 USC 112(b) below). The language “up to 400 amino acids in length” means any number of amino acids from 1-400. Furthermore, the language “at least 95% identity to the corresponding amino acid residues of SEQ ID NO:10” could mean that a polypeptide having 95% sequence identity to the entire length of SEQ ID NO:10 is required, or could mean that any number of amino acids up to 400 must have at least 95% identity with a similar number of amino acids in SEQ ID NO:10, but that no minimum number of amino acids required. It is therefore unclear how many amino acids are required from the sequence of SEQ ID NO:10, and any number of possible proteins could be encompassed. The newly added claims recite additional features including that the protein may not comprise a signal peptide, or may not have specific amino acid residues of SEQ ID NO:10.
The claimed inhibitors of ROR2 have required functions of treating osteoarthritis, cartilage loss, osteoarthritis associated pain, promoting cartilage repair and/or preventing cartilage degradation, as well as inhibiting ROR2. The inhibitor can comprise a further polypeptide domain that is also not adequately described, and which has the added function of enhancing the ability of the ROR2 inhibitor to treat osteoarthritis, cartilage loss, and/or osteoarthritis pain, promote cartilage repair and/or prevent cartilage degradation as compared to a corresponding ROR2 inhibitor which lacks the further polypeptide domain. The ROR2 inhibitor and the further polypeptide domain can be separated by a linker.
The specification discloses SEQ ID NO:10, which is an extracellular portion of ROR2, that can be included in the inhibitor. However the claims are not limited to SEQ ID NO:10, and instead can include any protein molecule which has up to 400 amino acids and shares at least 95% sequence identity with SEQ ID NO:10. This creates millions of proteins. For example, SEQ ID NO:10 is 406 amino acids long, and a 400 amino acid fragment could have up to 20 amino acids that are varied in the sequence, and any other amino acid can be substituted in the identified variable locations. This would produce as many as 3.75 x 1025 different proteins. The variability is further expanded because the claims are not limited to only sequences with 400 amino acids of SEQ ID NO:10, and can include any number of deletions, as well as additions and/or substitutions.
The encompassed inhibitors have no correlation between their structure and function. The claim requires that the inhibitors exhibit specific functions, but the specification provides no guidance regarding which proteins are capable of the required function. Further, the specification provides a single example that possesses the required functions, but this is not representative of the claimed vast genus of ROR2 inhibitor proteins. 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 polypeptides, 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, 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 a ROR2 protein inhibitor) 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 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 genus of proteins 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 not reasonably conclude that the full breadth of the claims 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.
The claims encompass an extremely genus of antibodies or fragments thereof that have required functions. 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 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 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 particular target, many of which have likely not been discovered. Relying on virtual screening also lends unpredictability to the art regarding identification of molecules that would be capable of the required functions of the instant claims. Guido et al teach that there are two main complex issues with predicting activity for a small molecule: accurate structural modeling and/or correct prediction of activity (see page 40). As taught by Clark et al (J. Med. Chem., 2014, 57 (12), pp 5023–5038), 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.
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).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai 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.
The 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 USPQ2dat1966.
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. Applicant has amended the claims to recite a ROR2 inhibitor that comprises a polypeptide having at least 95% identity to SEQ ID NO:10. Therefore the rejection should be withdrawn.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. The amendment to recite a protein having 95% SEQ ID NO:10 is not sufficient to overcome the rejection. As stated above, the claims are not limited to SEQ ID NO:10, and instead can include any protein molecule which has up to 400 amino acids and shares at least 95% sequence identity with SEQ ID NO:10. This creates millions of proteins given that SEQ ID NO:10 is 406 amino acids long, meaning that up to 20 amino acids can be varied in any variant sequence, and any other amino acid can be substituted in a desired location. This would produce as many as 3.75 x 1025 different proteins.
The encompassed inhibitors have no correlation between their structure and function. The claim requires that the inhibitors exhibit specific functions, but the specification provides no guidance regarding which proteins, peptides, antibodies, nucleic acids, small molecules or other agents are capable of the required function. Further, the specification provides a single example that possesses the required functions, but this is not representative of the claimed vast genus of ROR2 inhibitor proteins. For these reasons, and the reasons presented above, the rejection 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) 66, 69, 75, and 85-91 under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Bodine et al (WO 2004/094641 A2; filed 4/14/04; published 11/4/04) is maintained. The claim rejection has been updated to reflect the current claim amendments. The rejection of claims 67 and 76 is rendered moot by cancellation of the claims.
The instant claims are directed to a method of treating osteoarthritis, cartilage loss, osteoarthritis associated pain, promoting cartilage repair and/or preventing cartilage degradation comprising administering to a subject in need thereof a ROR2 inhibitor. The inhibitor can be a soluble fragment of a ROR2 protein. The ROR2 inhibitor can be formulated with a pharmaceutically acceptable carrier or excipient. The ROR2 inhibitor can comprise an affinity tag such as a GST tag and/or can be a protein with 50% sequence identity to SEQ ID NO:10.
Regarding the limitations of instant claims 66 and 85-87, Bodine teaches construction of ROR2 deletion mutant ROR2ΔC-Flag, which comprises the extracellular domain of ROR2 (see e.g. Figure 5A). This construct is designated by SEQ ID NO:12 (see e.g. page 12). Bodine teaches treatment of subjects comprising administering an agent which modulated target ROR molecule expression or activity (see e.g. claim 36), wherein the agent can be a polypeptide (see e.g. claim 43, and wherein the agent inhibits expression and/or activity of target ROR molecules (see e.g. claim 48). The term “treatment” refers to stimulating bone cell differentiation or bone formation, postponing development of bone disorders, reducing severity of disorders and symptoms that develop from a bone disorder (see e.g. page 46). The “treatment” is application or administration of an agent to a subject, wherein the agent can be in a therapeutic composition (see e.g. page 46). The disorder to be treated can be abnormal changes in bone metabolism that occurs in patients with osteoarthritis (see e.g. page 48). The treatment can include healing or regeneration of cartilage defects or injury (see e.g. page 50). Bodine teaches compositions for modulating bone-related activity comprising an effective amount of a ROR2 molecule (see e.g. claims 15 and 17). The term “ROR2 molecule refers to ROR polypeptides, fragments, variants and mutants thereof (see e.g. page 18 and 50). The ROR polypeptides can include SEQ ID NO:4, 6, 8, 10, and 12 (see e.g. page 28). These ROR polypeptides are considered “agents” (see e.g. page 50) and Bodine teaches that the agents can be administered to modulate bone-related activity (see e.g. page 49). The sequence of Bodine SEQ ID NO:12 has 100% sequence identity to instant SEQ ID NO:10 (see alignment below, instant SEQ ID NO:10 is designated as “Qy”, and Bodine SEQ ID NO:12 is designated as “Db” ). The protein of Bodine SEQ ID NO:12 would therefore inherently possess the functional properties of the instant ROR2 inhibitor protein. Further, the instant claims are directed to an inhibitor “comprising” a sequence that is 95% identical to instant SEQ ID NO:10. This open ended language indicates that other sequences can also be present in the inhibitor, and that the inhibitor is not required to be limited to the protein with sequence identity of instant SEQ ID NO:10. Therefore, while Bodine SEQ ID NO:12 may have additional amino acids present in the sequence, the existence of an identical sequence to instant SEQ ID NO:10 within Bodine SEQ ID NO:12 means that Bodine SEQ ID NO:12 reads on the instant claimed ROR2 inhibitor protein. Similarly, for claims 86 and 87, the fragment within Bodine would inherently comprise the required fragment of the named lengths and the sequence identity to specific segments of instant SEQ ID NO:10.
Query Match 100.0%; Score 2219; Length 436;
Best Local Similarity 100.0%;
Matches 406; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MARGSALPRRPLLCIPAVWAAAALLLSVSRTSGEVEVLDPNDPLGPLDGQDGPIPTLKGY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MARGSALPRRPLLCIPAVWAAAALLLSVSRTSGEVEVLDPNDPLGPLDGQDGPIPTLKGY 60
Qy 61 FLNFLEPVNNITIVQGQTAILHCKVAGNPPPNVRWLKNDAPVVQEPRRIIIRKTEYGSRL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FLNFLEPVNNITIVQGQTAILHCKVAGNPPPNVRWLKNDAPVVQEPRRIIIRKTEYGSRL 120
Qy 121 RIQDLDTTDTGYYQCVATNGMKTITATGVLFVRLGPTHSPNHNFQDDYHEDGFCQPYRGI 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 RIQDLDTTDTGYYQCVATNGMKTITATGVLFVRLGPTHSPNHNFQDDYHEDGFCQPYRGI 180
Qy 181 ACARFIGNRTIYVDSLQMQGEIENRITAAFTMIGTSTHLSDQCSQFAIPSFCHFVFPLCD 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ACARFIGNRTIYVDSLQMQGEIENRITAAFTMIGTSTHLSDQCSQFAIPSFCHFVFPLCD 240
Qy 241 ARSRAPKPRELCRDECEVLESDLCRQEYTIARSNPLILMRLQLPKCEALPMPESPDAANC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 ARSRAPKPRELCRDECEVLESDLCRQEYTIARSNPLILMRLQLPKCEALPMPESPDAANC 300
Qy 301 MRIGIPAERLGRYHQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFPELGG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 MRIGIPAERLGRYHQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFPELGG 360
Qy 361 GHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSCSPRDSSKMGILY 406
||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSCSPRDSSKMGILY 406
Regarding the limitations of claim 69, Bodine teaches that the ROR2 composition can comprise a pharmaceutically acceptable carrier (see e.g. claim 18).
Regarding the limitations of instant claim 75 and 88-89, Bodine teaches the sequence of SEQ ID NO:12, which is recited as the deduced amino acid sequence of Ror2bΔC-Flag protein (see e.g. page 12). The protein contains a Flag affinity tag (see e.g. page 7). The Flag affinity tag comprises 30 amino acids (see e.g. amino acids 407-435 of Bodine SEQ ID NO:12). The sequence of Bodine SEQ ID NO:12 comprises a sequence with 100% sequence identity to instant SEQ ID NO:10 (see alignment below, instant SEQ ID NO:10 is designated as “Qy”, and Bodine SEQ ID NO:12 is designated as “Db” ). The protein of Bodine SEQ ID NO:12 would therefore inherently possess the functional properties of the instant ROR2 inhibitor protein.
Query Match 100.0%; Score 2219; Length 436;
Best Local Similarity 100.0%;
Matches 406; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MARGSALPRRPLLCIPAVWAAAALLLSVSRTSGEVEVLDPNDPLGPLDGQDGPIPTLKGY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MARGSALPRRPLLCIPAVWAAAALLLSVSRTSGEVEVLDPNDPLGPLDGQDGPIPTLKGY 60
Qy 61 FLNFLEPVNNITIVQGQTAILHCKVAGNPPPNVRWLKNDAPVVQEPRRIIIRKTEYGSRL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FLNFLEPVNNITIVQGQTAILHCKVAGNPPPNVRWLKNDAPVVQEPRRIIIRKTEYGSRL 120
Qy 121 RIQDLDTTDTGYYQCVATNGMKTITATGVLFVRLGPTHSPNHNFQDDYHEDGFCQPYRGI 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 RIQDLDTTDTGYYQCVATNGMKTITATGVLFVRLGPTHSPNHNFQDDYHEDGFCQPYRGI 180
Qy 181 ACARFIGNRTIYVDSLQMQGEIENRITAAFTMIGTSTHLSDQCSQFAIPSFCHFVFPLCD 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ACARFIGNRTIYVDSLQMQGEIENRITAAFTMIGTSTHLSDQCSQFAIPSFCHFVFPLCD 240
Qy 241 ARSRAPKPRELCRDECEVLESDLCRQEYTIARSNPLILMRLQLPKCEALPMPESPDAANC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 ARSRAPKPRELCRDECEVLESDLCRQEYTIARSNPLILMRLQLPKCEALPMPESPDAANC 300
Qy 301 MRIGIPAERLGRYHQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFPELGG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 MRIGIPAERLGRYHQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFPELGG 360
Qy 361 GHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSCSPRDSSKMGILY 406
||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSCSPRDSSKMGILY 406
Regarding the limitations of instant claims 88 and 90, Bodine teaches the sequence of SEQ ID NO:12, which is recited as the deduced amino acid sequence of Ror2bΔC-Flag protein (see e.g. page 12). The protein contains a Flag affinity tag (see e.g. page 7). There are 30 additional amino acids in Bodine SEQ ID NO:12. The instant claims do not define the “further polypeptide domain”. But the instant specification does refer to “portion/domain” in the alternative. Therefore the term “further polypeptide domain” will be interpreted to read on any additional portion of a polypeptide. Further, the term “linker” is not defined in the specification. Therefore, any molecule, including a single amino acid, that binds two polypeptides portions together would meet the limitations of the claims. Bodine SEQ ID NO:12 includes amino acid sequences in addition to the sequence of instant SEQ ID NO:10. This indicates that an additional portion of a protein (i.e. further polypeptide domain), and at least one amino acid linking that portion to the sequence of instant SEQ ID NO:10 (i.e. a linker) are present, therefore reading on the broadest reasonable interpretation of the instant claims.
Regarding the limitations of instant claims 91, Bodine teaches construction of ROR2 deletion mutant ROR2ΔC-Flag, which comprises the extracellular domain of ROR2 (see e.g. Figure 5A). This construct is designated by SEQ ID NO:12 (see e.g. page 12). Bodine teaches treatment of subjects comprising administering an agent which modulated target ROR molecule expression or activity (see e.g. claim 36), wherein the agent can be a polypeptide (see e.g. claim 43, and wherein the agent inhibits expression and/or activity of target ROR molecules (see e.g. claim 48). The term “treatment” refers to stimulating bone cell differentiation or bone formation, postponing development of bone disorders, reducing severity of disorders and symptoms that develop from a bone disorder (see e.g. page 46). The “treatment” is application or administration of an agent to a subject, wherein the agent can be in a therapeutic composition (see e.g. page 46). The disorder to be treated can be abnormal changes in bone metabolism that occurs in patients with osteoarthritis (see e.g. page 48). The treatment can include healing or regeneration of cartilage defects or injury (see e.g. page 50). Therefore, Bodine anticipates treatment of osteoarthritis, and administration of the same protein inhibitor to the same patient population would inherently treat osteoarthritis associated pain.
Applicant’s Arguments
Applicant argues:
1. Bod