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 6/22/26 are acknowledged. Claims 1-19 and 21-59 are cancelled. New claims 60-78 are added. Claims 20 and 60-78 are pending. Claim 20 is amended. Claims 20 and 60-78 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statement filed on 6/22/26 has been considered. A signed copy is enclosed.
The reference lined through was not considered because the copy of the reference provided was illegible (see 37 CFR 1.98(a)).
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.
Terminal Disclaimer
The terminal disclaimer filed on 6/22/26 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent 12,228,580 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Withdrawn Objections
The objection to claims 4, 6, 8, and 10 because of the following informalities: the claims contain acronyms and/or abbreviations that should be spelled out upon first occurrence is rendered moot by cancellation of the claims.
The advisory that should claim 1 be found allowable, claim 20 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof is rendered moot by cancellation of claim 1.
New Objections
Claim Objections
Applicant is advised that should claim 76 be found allowable, claim 78 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Withdrawn Claim Rejections
The rejection of claim 20 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. The rejection of claims 1-19 is rendered moot by cancellation of the claims.
The rejection of claim 20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of Applicant’s amendments thereto. The rejection of claims 1-19 is rendered moot by cancellation of the claims.
The rejection of claim 12 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 claim.
The rejection of claim 20 under 35 U.S.C. 101 Claims 1-2, 4, 7-8, 14, 18-20, and 27-33 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more is withdrawn in light of Applicant’s amendments thereto. The rejection of claims 1-17 is rendered moot by cancellation of the claims.
The rejection of claim(s) 20 under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(1) as being anticipated by Bumol et al (WO 2022/232463 A1; filed 4/28/22; published 3/11/22) is withdrawn in light of Applicant’s amendments thereto. The rejection of claims 1-3, 5, 7, 9, 11-14, 16-18 is rendered moot by cancellation of the claims.
The rejection of claim(s) 20 under 35 U.S.C. 103 as being unpatentable over Richards et al (US 2019/0204316 A1; filed 3/11/19; published 7/4/19) is withdrawn in light of Applicant’s amendments thereto. The rejection of claims 1-13 and 16-17 is rendered moot by cancellation of the claims.
The rejection of claim 20 under 35 U.S.C. 103 as being unpatentable over Bumol et al (WO 2022/232463 A1; filed 4/28/22; published 3/11/22) in view of Ernst et al (Advanced Techniques in Diagnostic Microbiology. 2006:427–443) is withdrawn in light of Applicant’s amendments thereto. The rejection of claims 1-3, 5, 7, 9, and 11-18 is rendered moot by cancellation of the claims.
The rejection of claim 20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,402,391 in view of Bumol et al (WO 2022/232463 A1; filed 4/28/22; published 3/11/22) is withdrawn in light of Applicant’s amendments thereto. The rejection of claims 1-3, 5, 7, 9, 11-14 and 16-19 is rendered moot by cancellation of the claims.
The rejection of claim 20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,402,391 in view of Bumol et al (WO 2022/232463 A1; filed 4/28/22; published 3/11/22) and further in view of Ernst et al (Advanced Techniques in Diagnostic Microbiology. 2006:427–443) is withdrawn in light of Applicant’s amendments thereto. The rejection of claims 1-3, 5, 7, 9, and 11-19 is rendered moot by cancellation of the claims.
The rejection of claim 20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 12,228,580 is withdrawn in light of the Terminal Disclaimer filed on 6/22/26. The rejection of claims 1-14 and 16-18 is rendered moot by cancellation of the claims.
The rejection of claim 20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12,228,580 in view of Ernst et al (Advanced Techniques in Diagnostic Microbiology. 2006:427–443) is withdrawn in light of the Terminal Disclaimer filed on 6/22/26. The rejection of claims 1-18 is rendered moot by cancellation of the claims.
New 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.
Claims 71-78 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are directed to a method of assigning a post-infectious inflammatory disorder type for a subject suffering from a post-infectious inflammatory disorder, comprising assigning a post-infectious inflammatory disorder type for the subject based on a determined quantitative, multiplex cytokine/chemokine panel in a test sample from the subject. The post infectious inflammatory disorder can be a type selected from PASC, PTLD, and ME-CFS. The cytokine/chemokine panel can comprise three or more cytokines and/or chemokines, and the dependent claims set forth various species of biomarker combinations. The determining can be performed by several standard assays such as flow cytometry, mass spectrometry, protein array analysis, and other types of assays. The subject can further be administered a therapy such as an immunosuppressive, immune-modulator, or antiviral therapies to the subject.
There are at least two separate issues regarding written description in the instant claims.
First, the instant claims do not fully describe the required method, or present the required steps that would allow the method to achieve the required function. The specification provides no specific description of the steps involved, other than a generic introduction of possible assays that may work in the intended method. The specification further does not establish a reasonably specific threshold measurement, or specific units for the threshold, or corresponding controls that would identify any specific disease state, or that would distinguish disease states from one another in a patient. Further, the claims do not set forth steps to distinguish between different post-infectious inflammatory disorders. Thus the method described by the instant specification encompasses an overly broad genus, and there is no correlation between the steps of the method and the functional outcome. Therefore, the specification provides insufficient written description to support the genus encompassed by the claims.
Second, the claims recite genera of therapeutic agents without adequately describing said agents. For example, the claims recite the genera of “an inhibitor of C-C motif chemokine receptor 5 (CCR5) mediated CCL5 signaling” and “a CCR5 antagonist,” which are defined entirely by function without identifying a correlating structure. Applicant has amended the claims to increase the scope of the encompassed inhibitors to include any “inhibitor of C-C motif chemokine receptor 5 (CCR5) mediated CCL5 signaling.” This genus includes CCR5 and CCL5 antagonists and any other inhibitor of indirect targets within the CCR5/CCL5 signaling pathway. For example, Zeng et al (Genes & Diseases (2022) 9,12e27) shows in Figures 1, 2, and 3 that dozens of possible effector molecules are involved in the CCR5/CCL5 signaling pathway. Each of these molecules could be targeted by any of the encompassed molecule types described above. Further, the specification has not identified a sufficient number of species that would be representative of such broad genera of agents. The description of a limited number of examples of inhibitors which “work in a manner similar to maraviroc” is not sufficient to describe the enormous genus of compounds that are encompassed by the phrase “inhibitor of C-C motif chemokine receptor 5 (CCR5) mediated CCL5 signaling,” many of which may not have been yet discovered.
When the claims are given the broadest reasonable interpretation, the genera encompass proteins, peptides, nucleic acids, antibodies, small molecules, and any number of other types of agents.
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.)
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.
The skilled artisan cannot envision the steps, specific assay methods and specific measurement thresholds that are required to establish specific status outcomes. In general, the art regarding establishing biomarkers is unpredictable. Waiker et al (J Am Soc Nephrol. 2012 January; 23(1): 13–21) teach that although diagnostic tests are judged based on their ability to classify individuals according to disease status, the actual disease status is often not known with certainty in clinical medicine. It is also important to note that Waiker et al discuss the necessity of specific thresholds. Waiker et al describe that the measurement is common in medical practice, but the test can result in misclassification of disease status, and this may be specifically due to exclusion of certain intermediate values that may have led to an overestimation of the accuracy of other biomarkers. This indicates that the threshold established for any given biomarker to describe any particular disease is critical for establishing the accuracy of the biomarker to predict disease (see page 8). The instant disclosure fails to resolve the specific methods, the specific thresholds, or the correlation of Claudin-5 with any specific disease state. Because the genus may be so highly variant, the examples provided, as well as the generic terms of “using” Claudin-5 and “testing for mild cognitive impairment” are insufficient to describe the genus, even when considered in light of the general knowledge in the art.
Further, Mayeux (NeuroRx. 2004 Apr;1(2):182-8) teaches that while biomarkers provide a dynamic and powerful approach to understanding a spectrum of diseases, variability is a major concern in biomarkers (see abstract). Biomarkers are subject to critical timing regarding sample collection, storage conditions, and adequate laboratory handling (see Table 2). Further, normal ranges are often difficult to establish, given interindividual variability, tissue localization, reliability of the biomarker measurements, and persistence of the biomarker (see pages 187-188). This would make comparison to establish disease or select treatment highly unpredictable.
Biomarkers related to distinguishing responses to infection are complex and highly heterogenous. Nooijer et al (J Crit Care 78 (2023) 154360) teach that multiple inflammatory pathways could become activated upon an infection, with large interindividual differences (see e.g. page 14). On the one hand, a potentially involved pathway will not be expressed in every patient with a high mortality risk, whereas on the other hand, a patient with a high mortality risk will not express all pathways (see e.g. page 14). This makes that prognostication based on a single inflammatory biomarker is not likely to be reliable (see e.g. page 14). Another factor in variability is that the timing of biomarker measurement is highly relevant in its prognostic accuracy (see e.g. page 14).
Similarly Liu et al ( Nat Immunol 18, 1175–1180 (2017)) teach that many components contribute to inflammatory damage across a spectrum of diseases (see e.g. page 1179, right column). Reports of inconsistent results from biomarker-discovery research have been due in part to the lack of robust biomarker validation, lack of quality control and insufficient causal evidence linking inflammatory biomarkers to disease development (see e.g. page 1179, right column). Biomarker studies are hampered by the lack of reliable assays, scarce biospecimens and limited longitudinal data from the same subject (see e.g. page 1179, right column). These challenges make the translation of biomarker discovery to the clinic difficult (see e.g. page 1179, right column). Lai et al (Biomarkers in long COVID-19: A systematic review. Front. Med. 10:1085988) also demonstrate that identifying biomarkers for post-infectious conditions can be difficult. For example, Lai teaches that because of the heterogeneity of long COVID, no laboratory test could definitively distinguish long COVID from other diseases (see e.g. page 06). Unfortunately, many stressors, such as viruses, bacteria, inhaled nano/particles, industrial toxins, etc., do share common mechanistic features that involve inflammation via inflammasome activation (see e.g. page 08), suggesting that differentiating diseases based on a single set of biomarkers is unpredictable at best.
Applicant is advised that according to MPEP 2163, for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession.
Protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) As taught by Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cells (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity. 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 agents encompassed by the instant claims (see e.g. page 661, left column).
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 large number of polypeptide constructs that have specific required functions. The specification discloses two species of constructs (hz12E9v09 and hz16G10v11) within the instant claims scope that also have the required functions, but the specification does not provide any guidance as to which protein structures, sequences or individual amino acids are necessary, or can be varied, within the polypeptide and still retain the required functions.
The claims encompass an extremely genus of antibodies or antigen binding fragments thereof that have required functions. The specification discloses two closely related sub-genera of 5T4 VHH domains and anti-CD3 antibodies designated by SEQ ID NO for the required CDRs and VH/Vl. However, the claims are not so limited. 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.
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).
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 JAK or STAT, 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 JAK 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 JAK or STAT protein family member, or treat disease.
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. The specification describes inhibitors of CCR5 mediated CCL5 signaling include CCR5 antagonists and CCL5 antagonists. The specification describes maraviroc as having the required functions. The specification names other examples of CCR5/CCL5 interaction inhibitors which work in a manner similar to maraviroc. The specification also names two peptides and an anti-CCL5 antibody that are also capable of the required functions.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
Applicant has amended the claims to increase the scope of the encompassed inhibitors to include any “inhibitor of C-C motif chemokine receptor 5 (CCR5) mediated CCL5 signaling.” This can include CCR5 and CCL5 antagonists, but also includes any other inhibitor of indirect targets within the CCR5/CCL5 signaling pathway. For example, Zeng et al (Genes & Diseases (2022) 9,12e27) shows in Figures 1, 2, and 3 that dozens of possible effector molecules are involved in the CCR5/CCL5 signaling pathway. Each of these molecules could be targeted by any of the encompassed molecule types described above. The description of a limited number of examples of inhibitors which “work in a manner similar to maraviroc” is not sufficient to describe the enormous genus of compounds that are encompassed by the phrase “inhibitor of C-C motif chemokine receptor 5 (CCR5) mediated CCL5 signaling,” many of which may not have been yet discovered. Applicant has not set forth a structure that correlates with the required function for the extraordinarily broad genus encompassed in the claimed method. In the instant case, the functional characteristics are given without describing the correlation with a particular structure for the antibody. The specification provides no guidance regarding the structure that must be present for any given molecule to be capable of the required functions. Further, Applicant has not offered a representative number of species that show possession of the entire scope of the enormous genus of inhibitors recited in the claimed method. For these reasons, the rejection is maintained.
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 65, 69, 74-75, and 77 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 65 contains the term “(IL-10)” that is only referenced parenthetically. It is unclear, due to the presence of the parentheses, if the term is intended as a limitation of the claims, or is merely exemplary.
Claim 69 recites a “bead-based assay”. It is unclear what criteria must be met to be considered a “bead-based assay”.
Claims 74-75 recite “inhibitor of C-C motif chemokine receptor 5 (CCR5) mediated CCL5 signaling”. The scope of the inhibitors encompassed by the claim is indefinite. It is unclear if the inhibitor must bind to CCR5 or CCL5, or if the inhibitor could bind to molecules that indirectly target the signaling pathway.
Claim 77 recites “a test sample.” It is unclear if this “test sample” is the same as the “test sample” from the base claim, or is a different “test sample.”
Claims depending from the rejected claims do not remedy the deficiency and therefore are also rejected.
Applicant’s Arguments
Applicant argues:
1. Bead-based assay are described on page 14 of the specification and is a recognized term of art in the context of flow-cytometry methods.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
Page 14 of the specification does not define “bead-based assay.” The page provides example embodiments, but these embodiments are merely exemplary, and do not identify the metes or bounds of the term “bead-based assay.” Applicant has not provided evidence that the term “bead-based assay” is a term known in the art, and instead relies only on arguments. As stated in MPEP 2145, arguments presented by applicant cannot take the place of factually supported objective evidence. See, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Therefore, the argument is not persuasive and the rejection is maintained.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 74 and 77 are rejected 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.
Claim 74 recites “comprises administering an inhibitor…if the subject is assigned a PASC post-infectious inflammatory disorder type.” The claim therefore anticipated that some subjects will not be assigned a PASC post-infectious inflammatory disorder type, and therefore, for those subjects the claim offers no further limitation of the subject matter of the claim from which it depends.
Claim 77 requires measuring a multiplex cytokine and/or chemokine panel in a test sample obtained from the subject, which are limitations also recited in base claim 20, from which claim 77 depends. Therefore, claim 77 does not further limit the subject matter of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 71-73 and 76-78 are rejected under 35 U.S.C. 101 Claims 1-2, 4, 7-8, 14, 18-20, and 27-33 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements, which are recited at a high level of generality, provide conventional assays and samples that do not add meaningful limits to practicing the law of nature and abstract idea.
The Supreme Court in Mayo laid out a framework for determining whether an applicant is seeking to patent a judicial exception itself, or a patent-eligible application of the judicial exception. See Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. 66, 101 USPQ2d 1961). See MPEP 2106. The first step of the analysis asks whether the claimed invention is directed to a statutory category of invention. The instant claims recite a method of assigning a post-infectious inflammatory disorder type for a subject suffering from a post-infectious inflammatory disorder, comprising assigning a post-infectious inflammatory disorder type for a subject based on a determined quantitative, multiplex cytokine/chemokine panel in a test sample. The dependent claims name types of cytokines, chemokines, types of test samples, and types of assays to measure expression of the chemokines and cytokines. The claim is directed to a method, which is a statutory category of invention and therefore meets the requirements of the first step of the analysis.
Second, the claimed invention also must qualify as patent-eligible subject matter, i.e., the claim must not be directed to a judicial exception unless the claim as a whole includes additional limitations amounting to significantly more than the exception (see MPEP 2106). Based upon an analysis with respect to the claim as a whole, the instant claims are determined to be directed to a law of nature/natural principle and an abstract idea. The relationship between the recited biomarkers and a post-infectious inflammatory disorder, is a natural principle, which is a judicial exception. The claimed method describes correlation of a particular biomarker with a particular natural disease state, which is comparable to concepts identified by the Supreme Court in Mayo. (see Mayo 101 USPQ2d at 1966). Further, the decision-making required to identify a post-infectious inflammatory disorder type for a subject suffering from a post-infectious inflammatory disorder is a mental process that can be performed in the human mind (see e.g. MPEP 2106.04(a)). Claims to comparison of data, such as the measurements for the chemokines and/or cytokines, to determine existence of a disease type, can practically be performed in the human mind, which means they fall within the judicial exception of abstract ideas (see e.g. MPEP 2106.04(a)).
Third, a claim that focuses on the use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, or added something significant to, the natural principle itself. See Mayo 101 USPQ2d at 1966. Adding steps to a natural biological process that only recite well-understood, routine, conventional activity previously engaged in by researchers in the field would not be sufficient. See id. At 1966, 1970. The instant claims identify sample types (e.g. blood, tissue, or combination thereof) for testing, subjects to be tested, and well-known assays for determining protein product expression levels. The identification of sample types and subjects from which the samples are to be collected is routine in the art of medical testing. As stated in MPEP 2106.05(d), the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity. Determining the level of a biomarker in blood by any means has been determined as one of the well-understood, routine, conventional activity: see Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017). Regarding the assays to detect protein expression products, the assays claimed are routine in the art for measuring protein expression. This is acknowledged by the instant specification, which states that "Any convenient method of determining amounts of the cytokines/chemokines in the test sample may be employed, where various methods of determining amounts of cytokines/chemokines in a sample are known in the art and can be used in the methods disclosed herein” (see page 13). Therefore, the additional features of the claims (i.e., measuring the level of the recited biomarkers, and identifying the source of the sample for screening) do not ensure that the claims amount to significantly more than the natural principle itself. The claims use conventional means to observe a natural correlation and therefore the steps of the claimed methods are not sufficient to transform unpatentable natural correlations into patentable applications of those regularities. This is also supported by the findings of the in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 115 USPQ2d 1152 (Fed. Cir. 2015), wherein the Federal Circuit held that claims that measure biological substances using methods that are routine and conventional do not amount to more than reliance on a correlation that is a law of nature for patentability.
The question of whether identification of the patient population amounts to significantly more than the judicial exception is addressed in Mayo Collaborative Serv. v. Prometheus Labs., Inc., 566 U.S. _, 132 S. Ct. 1289, 1293-94, 101 USPQ2d 1961, 1965-66 (2012) (citing Diehr, 450 U.S. at 187, 209 USPQ at 7), when the Supreme Court determined that process claims reciting a correlation may inhibit further discovery by improperly tying up future use of laws of nature, even though the laws of nature at issue are narrow laws that may have limited applications. After measurement of the correlation, the claims can tie up a doctor's subsequent treatment decisions, whether treatment does or does not change in light of inference the doctor has drawn using disclosed correlations, since the claims threaten to inhibit development of more refined treatment recommendations that combine the patentee's correlations with later discovered features, and since the correlation step of the claims is set forth in highly general language covering all processes that make use of the correlation. Further, the steps simply refer to a relevant patient population, which is a pre-existing audience; doctors wish to determine whether a particular patient has a disease, or if the disease has/has not progressed. The claims inform a relevant audience about certain laws of nature; and additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community, and those steps, when viewed as a whole, add nothing significant beyond the sum of the parts taken separately. Even though the laws of nature at issue are narrow laws that may have limited applications, the claim does not amount to significantly more than the natural law itself.
Applicant’s Arguments
Applicant argues:
1. Applicant has amended the claims to recite a method that is not directed to a judicial exception. Withdrawal of the rejection is requested.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
New claims have been added that are directed to a judicial exception, particularly requiring a correlation of biomarkers to “assignment” of a disease diagnosis. Therefore, the rejection is proper for the newly added claims as indicated above.
Conclusion
Claims 20, 60-64, 66-68, and 70 are allowed.
Claims 65, 69, and 71-78 are not allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674 /BRIAN GANGLE/Primary Examiner, Art Unit 1645
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