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 .
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.
Withdrawn Objections
The objections to the specification are withdrawn in response to the amendments.
The objection to claim 3 is withdrawn in response to the amendments.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/ US2020/039884, filed 6/26/2020, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/867,194, filed 6/26/2019.
Status of the Claims
Claims 1-4, 6-13, 18-19 and 21 are pending; claims 1, 3-4, 11 and 21 are amended, claims 5, 14-17 and 20 are canceled; claim 19 is withdrawn. Claims 1-4, 6-13, 18 and 21 are examined below.
Maintained Rejection
Claim Rejections - 35 USC § 112
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.
Claim 4 is 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 4, as currently amended, recites “the level of the antibody is at least about 5%, higher in said test sample compared to a normal control”.
However, “at least about 5%, higher” is not clear. The term “about” in claim 4 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Furthermore, the limitation “at least about” is indefinite because it recites “at least” and “about”, i.e. it reads on an approximation of an approximation, which is not clear. A person having ordinary skill in the art would not be able to recognize what are the metes and bounds of the “at least about 5%, higher” level claimed. Note that amending the claim to recite “at least 5% higher” or “about 5% higher” would address the rejection.
Maintained Rejections
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 1-4, 6-13, 18 and 21 are rejected under 35 U.S.C. 101 because the claims are directed to at least one judicial exception without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
Prong One asks does the claim recite an abstract idea, law of nature, or natural phenomenon? In Prong One examiners evaluate whether the claim recites a judicial exception, i.e. whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim. While the terms "set forth" and "described" are thus both equated with "recite", their different language is intended to indicate that there are two ways in which an exception can be recited in a claim. For instance, the claims in Diehr, 450 U.S. at 178 n. 2, 179 n.5, 191-92, 209 USPQ at 4-5 (1981), clearly stated a mathematical equation in the repetitively calculating step, and the claims in Mayo, 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012), clearly stated laws of nature in the wherein clause, such that the claims "set forth" an identifiable judicial exception. Alternatively, the claims in Alice Corp., 573 U.S. at 218, 110 USPQ2d at 1982, described the concept of intermediated settlement without ever explicitly using the words "intermediated" or "settlement." See MPEP 2106.04 (II)(A)(1).
The claims recite “[a] method of diagnosing and treating Lyme disease” (claim 1) or “[a] method of detecting and treating post-treatment Lyme disease syndrome (PTLDS) or Lyme disease” (claim 11) or “[a] method for determining the efficacy of a therapeutic regimen in a subject having Lyme disease” (claim 21) “…comprising…” “assaying the sample for” (claim 1) or “detecting in the sample” (claim 11) or “a) detecting the presence of” (claim 21) “…antibodies to antigens from Borrelia burgdorferi…or … antigens from Borrelia burgdorferi, wherein the antigens comprise microcolony persister form antigens (MPA), in combination with detecting antibody to C6 peptide comprising (MKKDDQIAAAIA LRGMAKDGKFAVKDGE (SEQ ID NO: 1)” “in the subjected prior to the initiation of treatment…[or] after the initiation of therapeutic regimen” (claim 21) “and diagnosing the subject with Lyme disease when detection of antibodies to MPA or the MPA in the sample is observed” (claim 1) or “wherein detection of the antibodies or antigens in the sample is indicative of PTLDS or Lyme disease” (claim 11) or “wherein a decrease in the antibodies or antigens is a positive indicator of the efficacy of the therapeutic regimen” (claim 21).
The natural relationship to which the claims are directed (i.e., the relation between antibodies to antigens from Borrelia burgdorferi (including MPA) and Lyme disease and/or antigens from Borrelia burgdorferi (including MPA) and Lyme disease) is a law of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring levels of antibodies to antigens/ antigens from Borrelia burgdorferi (MPA) and the presence of Lyme disease.
The correlation between antibody/antigen levels and disease is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility. Similarly, it is a naturally occurring phenomenon that antibody/antigen levels are elevated to different extents in Lyme disease vs. in other disorders.
Dependent claims 2-3, 8-9 and 12-13 merely narrow the sample used in the natural correlation therefore are not sufficient to provide eligibility on its own.
Furthermore, the claimed steps of diagnosing Lyme disease if the level of the antibody is at least…compared to a normal control (claim 4) may also be categorized as abstract ideas, namely mental processes/ concepts performed in the human mind (such as a doctor simply thinking about the measured level of antibodies/antigens in relation to a cutoff value and making an evaluation, judgment, or opinion). The claims, under their broadest reasonable interpretation, cover performance of identifying risk solely within the human mind, or by a human using pen and paper. Comparing information regarding a sample to a control or target data (in this case, comparing a numerical level to a cutoff value) represents abstract ideas.
Similar concepts involving comparing information regarding a sample or test subject to a control or target data have been held to be an "abstract mental process", as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014) which involved "comparing BRCA sequences and determining the existence of alterations", the collecting and comparing of known information in Classen, the comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC, as well as Mayo (which also involved specific numerical cutoff levels).
Furthermore, claims 6-7 merely narrow the disease to which the natural correlation is directed to therefore are not sufficient to provide eligibility on its own.
Step 2A, Prong 2
The above-discussed steps of “detecting/diagnosing Lyme disease” and “comparing” the antibody/antigen levels to cutoff values are insufficient to integrate into a practical application because steps corresponding to mental activity, which could be performed in a practitioner’s head, are insufficient to constitute a practical application. In this case, detecting disease and comparing numerical values, represent judicial exceptions and not a practical application thereof.
The claims also recite “obtaining a sample from a subject” (claim 1 and 11). This limitation is drawn to data gathering steps, considered insignificant presolution activity.
Claims 1, 11, 18 and 21 recite “in combination with detecting antibody to C6 peptide comprising (MKKDDQIAAAIA LRGMAKDGKFAVKDGE (SEQ ID NO: 1)” (claims 1, 11 and 21) or “further comprising detecting antibody to C6 peptide comprising (MKKDDQIAAAIA LRGMAKDGKFAVKDGE (SEQ ID NO: 1) in combination with detecting the antibody or antigens” (claim 18). These limitations are drawn to data gathering steps, considered insignificant presolution activity.
Furthermore claim 10 recites “wherein said assaying comprises an enzyme-linked immunosorbent assay (ELISA), an antigen capture assay, flow cytometry, immunoblot, lateral flow assay (LFA), a Western blot, a mass spectrometry assay, immunoprecipitation, immunodiffusion, quantum dot, immunocytochemistry, radioimmunoassay, or any combination thereof”.
Such steps of providing a sample and measuring the concentration of antibodies/antigens therein using generic techniques does not go beyond insignificant presolution activity, i.e., a mere data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Furthermore, the steps of assaying the sample are recited at a high level of generality and are not tied, for example, to any particular machine or apparatus.
Claims 1 and 11 further recite “administering to the subject diagnosed with Lyme disease a therapeutic agent; thereby, diagnosing and treating Lyme disease in the subject” (claim 1), “administering to the subject a PTLDS or Lyme disease therapeutic agent” (claim 11).
These “treating” steps are insufficient to integrate the judicial exception as they are not limited to a particular treatment.
The step of “administering to the subject” a “therapeutic agent” is recited at a high level of generality and is not limited to a particular treatment agent. Such highly generalized treatment limitations – which do not require any specific therapeutic agent – do not amount to sufficient practical application to provide patentability. Although a claim limitation can integrate a judicial exception by applying or using the judicial exception(s) to effect a particular treatment or prophylaxis for a disease or medical condition, in this case no specific or particular therapeutic agent or treatment is set forth.
The level of generality in the instant claims stands in contrast to the treatment claims found patent-eligible in Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117 (Fed. Cir. 2018) and Natural Alternatives Int’l v. Creative Compounds LLC, 2017 WL 1216226 (Fed. Cir. Mar. 15, 2019). The claims at issue in Vanda recited administering a specific drug (iloperidone) at specific dosage ranges based on a patient’s genotype. Vanda, 887 F.3d at 1135. Accordingly, the court found that although the inventors recognized the relationships between iloperidone, a patient’s genotype, and QTc prolongation, what they claimed is “an application of that relationship,” i.e., “‘a new way of using an existing drug’ that is safer for patients because it reduces the risk of QTc prolongation.” Id. (quoting Mayo, 566 U.S. at 87). The Federal Circuit characterized the Vanda claims as being directed to “a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome.” Id. at 1136. Similarly, the Federal Circuit found that the claims in Natural Alternatives “contain specific elements that clearly establish they are doing more than simply reciting a natural law,” such as specifying a patient population, particular results to be obtained, specific compounds to be administered to achieve the claimed results, and dosages via an “effective” limitation. Natural Alternatives, 4-5.
In contrast to the claims in Vanda and Natural Alternatives, the present claims do not specify a particular result to be obtained, a compound to be administered to achieve a claimed result, or any specific dosage of a specific compound.
Rather, “administering to the subject diagnosed with Lyme disease a therapeutic agent; thereby, diagnosing and treating Lyme disease in the subject” (claim 1) and “administering to the subject a PTLDS or Lyme disease therapeutic agent” (claim 11) would be directed to any and all therapeutic agents related with Lyme disease. The recited treating steps do not limit the claims to a particular application; instead, the effect of the treatment limitations “is simply to tell doctors to apply the law somehow when treating their patients.” Mayo, 566 U.S. at 81-82.
Here, the claimed treatment step is instead merely an instruction to “apply” the exception in a generic way. Thus, the treatment step does not integrate the judicial exception(s) into a practical application.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of the claims, including the steps of providing a fluid sample and assaying/detecting the level of antibodies/antigens therein, do not add significantly more to the judicial exception(s). The step of assaying recited at a high level of generality and is not limited, for example, to any specific testing technique.
In this case, it was well-understood, routine and conventional to assay a sample using the recited generic techniques of dependent claim 10. See for example Embers et al. Diagnostic Laboratory Immunology, April 2016 Volume 23 Issue 4, https://doi.org/10.1128/CVI.00685-15 (Cite No. 2 of IDS filed 12/22/2021) (“Embers”) teaches that “[t]he two most commonly used tests for diagnosis of Lyme disease in North America are (i) the two-tier test that includes an enzyme-linked immunosorbent assay (ELISA) and confirmatory Western blotting and (ii) the C6 test, where antibodies to a specific peptide within a conserved region of VlsE, the B. burgdorferi antigen, are detected” (page 294 column 1 paragraph 2).
Also, Gilbert et al. (US 20190128887 A1) (Cite No. 1 of IDS filed 12/22/2021) (“Gilbert”) teaches that “[t]he microwell plate is a standard tool in clinical diagnostic testing laboratories. A very common usage is in the enzyme-linked immunosorbent assay (ELISA)” (paragraph 38).
See also Jasson et al. Clinical Microbiology and Infection Volume 11, Issue 2, February 2005, Pages 147-150, https://doi.org/10.1111/j.1469-0691.2004.01041.x (Cite No. 1 of IDS filed 12/22/2021) (“Jasson”) teaches, with respect to Lyme disease, that “[a]nalysis by Western immunoblotting (WB) is suitable for confirming the results of serological screening methods [1, 2]. A two-step approach, comprising an enzyme-linked immunosorbent assay (ELISA), and subsequent confirmation by WB, has been recommended in the USA [3] and Europe” (page 148 column 1 paragraph 1).
Furthermore, there is evidence that detecting antibody to C6 peptide and administering a therapeutic agent is well-understood, routine and conventional in the art.
Embers (Cite No. 2 of IDS filed 12/22/2021) further teaches that “[t]reatment with antibiotics is generally effective, even more so when employed soon after infection… The two most commonly used tests for diagnosis of Lyme disease in North America are… and (ii) the C6 test, where antibodies to a specific peptide within a conserved region of VlsE, the B. burgdorferi antigen, are detected (5–8)….C6 tests exhibit high specificity and are most sensitive for patients in the disseminated phases of disease (5, 8–10)…the C6 test has been evaluated as an indicator of treatment outcome in the United States (11, 12), with a ≥4-fold decline in antibody titer (up to 6 months after treatment) in a majority of patients” (page 294 col. 1 paras. 1-2).
Furthermore, Levy et al. CLINICAL AND VACCINE IMMUNOLOGY, Jan. 2008, p. 115–119 doi:10.1128/CVI.00340-07 (“Levy”) teaches that “[t]he detection of antibody to the Borrelia burgdorferi C6 peptide by use of enzyme-linked immunoassays is a widely accepted method for the diagnosis of Lyme disease spirochete infection in dogs and in humans… A quantitative assay for determining C6 antibody levels was developed and used to measure changes in antibody levels following antibiotic treatment of B. burgdorferi” (Abstract).
Also, the specification page 32 lines 18-22 suggest that administering to the subject diagnosed with Lyme disease a therapeutic agent is well-understood, routine and conventional in the art (“the methods for diagnosing and treating Lyme disease, in particular early stage Lyme disease, and post-treatment Lyme disease syndrome (PTLDS) comprise administering … readily known treatments”).
See also Richards et al. (WO 2017119881 A1) (“Richards”). Richards teaches “[a] method of differentiating, diagnosing, and treating Lyme disease in a subject comprising the steps of: obtaining a sample from the subject; detecting in the sample the presence of a biomarker signature differentiating LD from other diseases with similar symptoms; and administering a therapeutic treatment to the subject based on the biomarker signature detection results” (claim 1). Richards further teaches “wherein the therapeutic treatment comprises administration of a pharmaceutical composition” (claim 12), which reads on the Lyme disease therapeutic agent claimed.
Furthermore, detecting antibody to C6 peptide comprising SEQ ID NO: 1 is also well-understood, routine and conventional in the art.
For example, Mejan and Levet (FR 2949472 A1) ("Mejan") teaches “proteins…and a method and kit for the in vitro diagnosis of Lyme Borreliosis using said proteins” (Abstract). Mejan further teaches detecting antibody to C6 peptide comprising MKKDDQIAAAIA LRGMAKDGKFAVKDGE (SEQ ID NO: 1) ( “the subject of the present invention is a method for diagnosis In vitro of a Lyme Borreliosis in a biological sample (for example a sample of serum, blood, plasma, etc.), according to which the biological sample is brought into contact with at least one protein such as defined above and one determines if there is formation of a complex Immunologically between said protein and antibodies of the biological sample (IgGs and / or IgMs)” page 5 paragraphs 5-7, “[t]he protein comprises or consists of a sequence identified as SEQ ID NO: 38” page 7 paragraph 1). Note that SEQ ID NO: 38 of Mejan is 100% matched to SEQ ID NO: 1 of the instant claims.
Similarly, Levet and Mejan (US 20120156694 A1) (“Levet”) teaches detecting the antibody to C6 peptide comprising SEQ ID NO: 1 for diagnosis of Lyme (“The protein of the invention can in particular be used for the diagnosis of a Borrelia infection…according to which the biological sample is brought into contact with at least one protein as defined above and it is determined whether there is formation of an immunological complex between said protein and antibodies of the biological sample (IgGs and/or IgMs)” para. 38, “The preferred chimeric proteins of the invention are particularly identified as comprising (or consisting essentially of or consisting of) a sequence selected from SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 23; the most preferred protein being that which comprises or which consists of a sequence identified in SEQ ID NO: 20 in the sequence listing” para. 24). Note that SEQ ID NOs: 20-21 and 23 of Levet are all 100% matched to SEQ ID NO: 1 of the instant claims.
In view of the above evidence, the claimed steps assay generic techniques and treatments that do not add any feature that is more than well-understood, purely conventional, or routine in the field of clinical diagnostics and biochemical assay methodologies involving treatments.
Furthermore, every application of the judicial exception would require assaying/detecting of the level of antibodies/antigens from Borrelia burgdorferi in a sample. Limitations that are necessary for all practical applications of a judicial exception, such that everyone practicing the judicial exception would be required to perform those steps or every product embodying that judicial exception would be required to include those features, would not be sufficient to confer patent eligibility. In this case, everyone practicing the judicial exception would need to determine the level of antibodies/antigens.
When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention, and at the time the application was filed, e.g., the routine and conventional techniques of detecting a protein using an antibody to that protein. See also MPEP 2106.05(g).
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
New Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-4, 6-13, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Jacek et al. J Immunol (2016) 196 (3): 1036–1043, https://doi.org/10.4049/jimmunol.1501861 (“Jacek”)-(Cite No. U of PTO 892 6/4/2025) in view of Feng et al. Front. Microbiol., 09 February 2016 Sec. Antimicrobials, Resistance and Chemotherapy Volume 7 - 2016 | https://doi.org/10.3389/fmicb.2016.00062 (“Feng”) (Cite No. V of PTO 892 6/4/2025), Richards et al. (WO 2017119881 A1) (“Richards”) and Mejan and Levet (FR 2949472 A1) ("Mejan") (Cite No. N of PTO 892 6/4/2025).
Regarding claims 1, 7, 11 and 18, Jacek suggests a method of diagnosing Lyme disease in a subject, and detecting post-treatment Lyme disease syndrome (PTLDS) or Lyme disease, (“Epitope-Specific Evolution of Human B Cell Responses to Borrelia burgdorferi VlsE Protein from Early to Late Stages of Lyme Disease” Title, “Our findings have implications for gaining a more nuanced understanding of the evolution of the Ab response to VlsE in the context of B. burgdorferi persistence and its potential use as a source of information for staging the disease” page 1037 column 1 paragraph 2) comprising: obtaining a sample from the subject (“90 patients” Abstract, “Serum samples were obtained with written informed consent” page 1037 column 1 paragraph 3), assaying the sample for i) the level of antibodies to antigens from Borrelia burgdorferi (“IgG Abs against the specific IR6, N-terminal, and C-terminal immunoreactive sequences were measured separately by ELISA” page 1039 column 1 paragraph 4), wherein the antigens comprise microcolony persister form antigens (MPA) (“VlsE is a surface lipoprotein of B. burgdorferi that undergoes antigenic variation during infection” page 1036 column 2 paragraph 2, “in the context of B. burgdorferi persistence” page 1037 column 1 paragraph 2, “There is evidence that VlsE is required for optimal infectivity and persistence of the spirochete in the mammalian host” page 1042 column 1 paragraph 1), and diagnosing the subject with Lyme disease when detection of antibodies to MPA is observed (“Ab reactivity to the membrane-proximal N- and C-terminal epitopes of VlsE (VlsE21 and VlsE336) increased sharply from early to late Lyme disease (Fig. 2E, 2F, Table II)….whereas none of the healthy controls were positive” page 1040 column 2 paragraph 3, see Figs. 2-4), wherein detection of the antibodies or antigens in the sample is indicative of PTLDS or Lyme disease ( “some patients experience persistent symptoms … after standard antibiotic treatment and in the absence of evidence for ongoing infection (8–10). The condition, referred to as posttreatment Lyme disease syndrome” page 1036 column 2 paragraph 1, “It was hypothesized that Abs against the N- and C-terminal epitopes may be associated with later manifestations and more intractable forms of Lyme disease that would be more likely to lead to persistence of symptoms in some individuals…the Ab response to VlsE in the context of B. burgdorferi persistence and its potential use as a source of information for staging the disease” page 1037 column 1 paragraphs 1-2, “Ab reactivity to the membrane-proximal N- and C-terminal epitopes of VlsE (VlsE21 and VlsE336) increased sharply from early to late Lyme disease… whereas none of the healthy controls were positive” page 1040 column 2 paragraph 3, “It is possible that this is another protective mechanism of the spirochete for persistence in the human host” page 1042 column 1 paragraph 3). Note that although Jacek fails to use the language MPA, Jacek suggests MPA when teaching that “VlsE is a surface lipoprotein of B. burgdorferi that undergoes antigenic variation during infection” and further uses the language “B. burgdorferi persistence”. Note that the specification page 22 lines 7-8 define the “term “antigen” as…a protein or polypeptide capable of generating an immune response in the form of an antibody”. Therefore, Jacek suggests that VlsE is MPA. Furthermore, although Jacek fails to use the language diagnosing Lyme disease or PTLDS, Jacek suggests these limitations when teaching that VlsE antibodies are a biomarker of Lyme disease and can be used to stage the disease. Furthermore Jacek suggests diagnosing PTLDS because Jacek teaches that late disease patients may develop PTLDS, hypothesizes that Abs against the N- and C-terminal epitopes of VlsE may be associated with Lyme disease and persistence of symptoms in some individuals, and showing that Ab reactivity to the membrane-proximal N- and C-terminal epitopes of VlsE (VlsE21 and VlsE336) increased sharply from early to late Lyme disease and none of the healthy controls were positive. Jacek further teaches that “C6, a peptide that reproduces the IR6 epitope, is now used in a commercial diagnostic test (23)” (page 1037 column 1 paragraph 1). Jacek further teaches detecting the antibody to “VlsE274 (aa 274–298, representing the IR6 epitope: MKKDDQIAAAIA LRGMAKDGKFAVK)” (page 1037 column 1 paragraph 1, see Figs. 2 and 4).
Jacek fails to explicitly teach that the VlsE antigen from Borrelia burgdorferi, which contributes to Borrelia burgdorferi persistence, is “microcolony persister form antigens”. Jacek also fails to explicitly teach diagnosing Lyme Disease/PTLDS. Jacek fails to further teach treating Lyme disease or PTLDS comprising administering to the subject diagnosed with Lyme disease a PTLDS or Lyme disease therapeutic agent, thereby diagnosing and treating Lyme disease. Jacek fails to teach further detecting antibody to C6 peptide comprising MKKDDQIAAAIA LRGMAKDGKFAVKDGE (SEQ ID NO: 1), i.e., Jacek fails to teach the last 3 amino acids of SEQ ID NO: 1.
Feng teaches that persisters in the context of Borrelia burgdorferi are MPA (“Borrelia burgdorferi develops persisters stochastically in stationary phase which are tolerant to the antibiotics used to treat Lyme disease…In stationary phase cultures (7– 15 days old), increased numbers of atypical forms such as round bodies and aggregated biofilm-like microcolonies develop” page 2 column 1 paragraph 3). Feng further suggests that MPAs are biomarkers of Lyme disease/PTLDS, i.e. diagnosing Lyme disease/PTLDS (“Borrelia burgdorferi is the causative agent of Lyme disease, which is the most common vector-borne disease in the United States with an estimated 300,000 cases in 2013…at least 10–20% of Lyme disease patients experience prolonged symptoms… 6 months after antibiotic treatment, a collection of symptoms called Post-Treatment Lyme Disease Syndrome” page 2 column 1 paragraph 1, “The cause of PTLDS is unknown, though there are several theories including co-infections (Swanson et al., 2006), autoimmune response (Steere et al., 2001), immune response to continued presence of antigenic debris (Bockenstedt et al., 2012), as well as B. burgdorferi persisters that are not killed by the current antibiotics” page 2 column 1 paragraph 2). Note that PTLDS is reasonably considered a species of Lyme disease given that it is the term given to “a collection of symptoms” in Lyme disease patients.
Richards teaches “biomarker signatures for Lyme disease differentiation and methods of use thereof” (Title). Richards further teaches “[a] method of differentiating, diagnosing, and treating Lyme disease in a subject comprising the steps of: obtaining a sample from the subject; detecting in the sample the presence of a biomarker signature differentiating LD from other diseases with similar symptoms; and administering a therapeutic treatment to the subject based on the biomarker signature detection results” (claim 1). Richards further teaches “wherein the therapeutic treatment comprises administration of a pharmaceutical composition” (claim 12), which reads on the Lyme disease therapeutic agent claimed. Richards further suggests that the treatment step prevents severe symptoms in the future (“Differentiation and diagnosis are important because early and appropriate treatment have the greatest chance of a cure; delayed treatment is associated with the severe chronic form of the disease. LymeDisease.org published a Health Policy paper based on a survey of Lyme patients, many of whom might not have had such severe symptoms had they been diagnosed and treated promptly,” page 13 lines 17-22).
Mejan teaches “proteins…and a method and kit for the in vitro diagnosis of Lyme Borreliosis using said proteins” (Abstract). Note that Mejan teaches that Lyme Borreliosis is Lyme disease (“Lyme Borreliosis (LB) is a non-contagious infectious disease caused by a spirochaete called Borrelia burgdorferi, transmitted to humans by a tick bite of the genus Ixodes. LB causes, without treatment, various pathological disorders (dermatological, arthritic, cardiac, neurological and sometimes ocular). It is the most common vector disease in the USA and some temperate countries of the Northern Hemisphere” page 2 paragraph 2). Mejan further teaches detecting antibody to C6 peptide comprising MKKDDQIAAAIA LRGMAKDGKFAVKDGE (SEQ ID NO: 1) ( “the subject of the present invention is a method for diagnosis In vitro of a Lyme Borreliosis in a biological sample (for example a sample of serum, blood, plasma, etc.), according to which the biological sample is brought into contact with at least one protein such as defined above and one determines if there is formation of a complex Immunologically between said protein and antibodies of the biological sample (IgGs and / or IgMs)” page 5 paragraphs 5-7, “[t]he protein comprises or consists of a sequence identified as SEQ ID NO: 38” page 7 paragraph 1). Note that SEQ ID NO: 38 of Mejan is 100% matched to SEQ ID NO: 1 of the instant claims. Mejan further teaches that “[t]he present invention proposes to solve all the drawbacks of the state of the art, by new chimeric recombinant proteins, easily synthesizable and purifiable, and having a strong immunoreactivity vis-à-vis sera of patients likely to be infected with one or more pathogenic species of Borrelia burgdorferi” (page 3 paragraph 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Jacek to rely on MPA as a diagnostic/indicative biomarker of Lyme disease/PTLDS taught by Feng because Feng teaches a finite list of possible causes of PTLDS, which, as taught by Feng, diagnosing PTLDS is a current need in the field. Therefore, a person having ordinary skill in the art would have found it obvious to pick MPA from said finite list. One would be motivated to do this because Feng teaches that Lyme disease is the most common vector-borne disease in the United States and 10-20% of patients experience PTLDS. A person having ordinary skill in the art would have had a reasonable expectation of success because both Jacek and Feng are drawn to B. burgdorferi persisters in the context of Lyme disease and PTLDS.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Jacek in view of Feng to rely on the treating of Lyme disease by administering a Lyme disease therapeutic agent, thereby detecting/diagnosing and treating Lyme disease in the subject taught by Richards because Richards teaches that this prevent severe symptoms in the future. A person having ordinary skill in the art would have had a reasonable expectation of success because both Jacek in view of Feng and Richards are drawn to methods of diagnosing Lyme disease in a subject comprising obtaining a sample from the subject and assaying the sample for biomarkers.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Jacek in view of Feng and Richards to use SEQ ID NO: 1 taught by Mejan to detect antibodies to antigens from Borrelia burgdorferi in Jacek because Mejan teaches that this protein is easily synthesizable and purifiable and has a strong immunoreactivity to patient sera likely to be infected with one or more pathogenic species of Borrelia burgdorferi. A person having ordinary skill in the art would have had a reasonable expectation of success because Jacek teaches detecting antibody to C6 peptide comprising MKKDDQIAAAIA LRGMAKDGKFAVK, i.e. 89% matched to SEQ ID NO: 1.
Regarding claims 2 and 12, Jacek in view of Feng, Richards and Mejan teach the methods of claims 1 and 11 as discussed above.
Jacek further teaches wherein the sample is assayed for the level of antibodies to antigens from Borrelia burgdorferi, wherein the level of antibodies to antigens from Borrelia burgdorferi is detected (page 1039 column 1 paragraph 4).
Regarding claims 3 and 13, Jacek in view of Feng, Richards and Mejan teach the methods of claims 1 and 11 as discussed above.
Richards further suggests wherein the sample is assayed for the level of antigens from Borrelia burgdorferi, wherein the level of antigens from Borrelia burgdorferi is detected (“the present invention biomarker signature score may be combined with evidence of the LD spirochete obtained from other bodily fluids or cells including urine, blood, tears, saliva, or WBCs by… antibody detection of trapped antigens” page 8 lines 4-8). Richards further teaches that detecting the level of antigens from Borrelia burgdorferi “differentiate LD from other diseases presenting similar symptoms” (page 8 lines 8-9).
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Jacek in view of Feng, Richards and Mejan to include the assaying/detecting the level of antigens from Borrelia burgdorferi taught by Richards because Richards teaches that this enables the differentiation of Lyme disease from other diseases presenting similar symptoms. A person having ordinary skill in the art would have had a reasonable expectation of success because both Jacek in view of Feng, Richards and Mejan and Richards are drawn to methods of diagnosing Lyme disease in a subject comprising obtaining a sample from the subject and assaying the sample for biomarkers.
Regarding claim 4, Jacek in view of Feng, Richards and Mejan teach the methods of claim 1 as discussed above.
Jacek further teaches wherein said subject is diagnosed with the Lyme disease if the level of the antibody is at least about 5%, higher in said test sample compared to a normal control (see Figs. 2-4 of Jacek showing significant higher antibody levels compared to healthy controls).
Regarding claim 6, Jacek in view of Feng, Richards and Mejan teach the methods of claim 1 as discussed above.
Jacek further suggests wherein the Lyme disease comprises early Lyme disease (see Figs. 2-3 showing different level of antibodies with respect to disease stage).
Regarding claims 8-9, Jacek in view of Feng, Richards and Mejan teach the methods of claim 1 as discussed above.
Jacek further teaches wherein the sample comprises a bodily fluid from the subject, wherein the bodily fluid comprises whole blood, a component of whole blood, plasma, serum, urine, cerebrospinal fluid, or synovial fluid (page 1037 column 1 paragraph 3).
Regarding claim 10, Jacek in view of Feng, Richards and Mejan teach the methods of claim 1 as discussed above.
Jacek further teaches wherein said assaying comprises an enzyme-linked immunosorbent assay (ELISA) and immunoblot (page 1039 column 1 paragraph 4, “Immunoblotting” page 1040 column 1 paragraph 1, see Fig. 5).
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Embers et al. Diagnostic Laboratory Immunology, April 2016 Volume 23 Issue 4, https://doi.org/10.1128/CVI.00685-15 (Cite No. 2 of IDS filed 12/22/2021) (“Embers”) in view of Jacek, Feng and Mejan.
Embers suggests a method for determining the efficacy of a therapeutic regimen in a subject having Lyme disease (“At 4 months postinoculation (p.i.), five animals received antibiotic treatment consisting of one 25 mg tablet of doxycycline (Bio-Serv) administered twice a day for 28 consecutive days. …Blood was collected at 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 or 25, 30 or 31, 32 or 33, 34 or 35, 39, 47 or 48, 50, 58, and 69 weeks p.i.” page 295 column 2 paragraph 5, “FIG 2 Comparison of IgG antibody detection by ELISA to that by Multiplex assay in longitudinal samples from infected monkeys reveals sensitivity differences” see Fig. 2), the method comprising: a) detecting the presence of (i) antibodies to antigens from Borrelia burgdorferi in the subject prior to the initiation of treatment (“At 4 months postinoculation (p.i.), five animals received antibiotic treatment…Blood was collected at 0…weeks p.i.” page 295 column 2 paragraph 5 see Fig. 2); b) detecting the presence of (i) antibodies to antigens from Borrelia burgdorferi in the subject after initiation of the therapeutic regimen (see Fig. 2); and wherein a decrease in the antibodies is a positive indicator of the efficacy of the therapeutic regimen (“The ELISA indicated a steady decline to below baseline (the average of preimmune serum values) by week 30, whereas the Multiplex assay indicated that levels rose slightly after the beginning of treatment and did not drop below baseline until week 35; a low level of antibody was also detected at week 58 with the Multiplex assay” page 296 column 2 paragraph 2, “[t]he C6 test has been evaluated as an indicator of treatment outcome in the United States (11, 12), with a 4-fold decline in antibody titer (up to 6 months after treatment) in a majority of patients” page 294 column 1 paragraph 2). Note that although Embers fails to use the language “determining the efficacy of a therapeutic regimen [and] a decrease in the antibodies is a positive indicator of the efficacy of the therapeutic regimen”, the teaching that C6 test has been evaluated as an indicator of treatment outcome with a 4-fold decline in antibody titer (up to 6 months after treatment) in a majority of patients, and the showing of data of a decrease in antibody levels after treatment provides a method of determining the efficacy of a therapeutic regimen and suggests that a decrease in antibody levels is an indicator of treatment efficacy.
Embers fails to teach wherein the antigens comprise microcolony persister form antigens (MPA) and in combination with detecting the antibody to C6 peptide comprising MKKDDQIAAAIA LRGMAKDGKFAVKDGE (SEQ ID NO: 1).
Jacek suggests detecting the presence of antibodies to antigens from Borrelia burgdorferi (page 1039 column 1 paragraph 4), wherein the antigens comprise microcolony persister form antigens (MPA) (page 1036 column 2 paragraph 2, page 1037 column 1 paragraph 2, page 1042 column 1 paragraph 1). Jacek further teaches that “C6, a peptide that reproduces the IR6 epitope, is now used in a commercial diagnostic test (23)” (page 1037 column 1 paragraph 1). Jacek further teaches detecting the antibody to “VlsE274 (aa 274–298, representing the IR6 epitope: MKKDDQIAAAIA LRGMAKDGKFAVK)” (page 1037 column 1 paragraph 1, see Figs. 2 and 4). Jacek further teaches that “[t]he mean Ab response to the IR6 region (as detected by the
VlsE274 ELISA and the commercial C6 assay) for every Lyme disease subgroup (single EM, multiple EM, early neurologic, late neurologic, responsive arthritis, and refractory arthritis) was significantly higher than for the healthy control group (Fig. 2C, 2D)” (page 1040 col. 2 para. 2).
Feng teaches that persisters in the context of Borrelia burgdorferi are MPA (page 2 column 1 paragraph 3). Feng further suggests that MPAs are biomarkers of Lyme disease/PTLDS (page 2 column 1 paragraph 1, page 2 column 1 paragraph 2). Feng teaches that “[t]he cause of PTLDS is unknown, though there are several theories including co-infections (Swanson et al., 2006), autoimmune response (Steere et al., 2001), immune response to continued presence of antigenic debris (Bockenstedt et al., 2012), as well as B. burgdorferi persisters that are not killed by the current antibiotics” (page 2 column 1 paragraph 2).
Mejan teaches “proteins…and a method and kit for the in vitro diagnosis of Lyme Borreliosis using said proteins” (Abstract). Note that Mejan teaches that Lyme Borreliosis is Lyme disease (page 2 paragraph 2). Mejan further teaches detecting antibody to C6 peptide comprising MKKDDQIAAAIA LRGMAKDGKFAVKDGE (SEQ ID NO: 1) (page 5 paragraphs 5-7, page 7 paragraph 1). Note that SEQ ID NO: 38 of Mejan is 100% matched to SEQ ID NO: 1 of the instant claims. Mejan further teaches that “[t]he present invention proposes to solve all the drawbacks of the state of the art, by new chimeric recombinant proteins, easily synthesizable and purifiable, and having a strong immunoreactivity vis-à-vis sera of patients likely to be infected with one or more pathogenic species of Borrelia burgdorferi” (page 3 paragraph 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Embers to rely on the wherein the antigens are MPA taught by Jacek because Feng teaches that these are biomarkers of PTLDS, which as taught by Feng, diagnosing PTLDS is a current need in the field. One would be motivated to makes such a modification to receive the expected benefit of further diagnosing PTLDS. A person having ordinary skill in the art would have been further motivated to modify the teachings of Embers to include detecting antibody to C6 peptide taught by Jacek because Jacek teaches this is an effective biomarker for all stages of Lyme disease. Therefore, one would be motivated to include detecting antibody to C6 peptide in order to diagnose Lyme disease at any stage. A person having ordinary skill in the art would have had a reasonable expectation of success because both Embers and Jacek teach measuring the antibodies to antigens from Borrelia burgdorferi in a blood sample from a subjects with Lyme disease.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Embers in view of Jacek and Feng to use SEQ ID NO: 1 taught by Mejan to detect antibodies to antigens from Borrelia burgdorferi in Embers because Mejan teaches that this protein is easily synthesizable and purifiable and has a strong immunoreactivity to patient sera likely to be infected with one or more pathogenic species of Borrelia burgdorferi. A person having ordinary skill in the art would have had a reasonable expectation of success because Jacek teaches detecting antibody to C6 peptide comprising MKKDDQIAAAIA LRGMAKDGKFAVK, i.e. 89% matched to SEQ ID NO: 1.
Response to Arguments
Applicant's arguments filed 12/4/2025 have been fully considered but they are not persuasive.
Regarding the 101 rejections, Applicant argues that “[a]s applied to the instant application, amended Claims 1 and 11 include the steps conducted for "diagnosing" followed by treatment. The claims are thus directed to a method of treating, rather than being "directed" to a judicial exception and are integrated into a practical application, i.e. the step of administering of a pharmaceutical composition…Applicant has amended Claims 1 and 11 to require steps conducted in a laboratory and the treatment of the subject…For at least these reasons, Applicant submits that the pending claims are patent eligible under 35 U.S.C. § 101 because they are not directed to a judicial exception” (page 10 paras. 2 and 4 and page 11 para. 3). However, administering a therapeutic agent, is not considered to be a particular treatment, thus fails to integrate the judicial exception(s) into a practical application (see rejection above for a complete analysis).
Regarding the 103 rejections, Applicant argues that “Jacek fails to teach disclose or otherwise suggest the development of assays that combine the measurement of MPA antigens and antibodies” (page 15 para. 2). However, the claims recite “assaying” (claim 1) or “detecting” (claims 11 and 21) “…antibodies…and/or…antigens” (claims 1 and 11 (emphasis added)) or “…antibodies…or…antigens” (claim 21 (emphasis added)). Therefore, independent claims 1, 11 and 21 do not require assaying/detecting both antibodies and antigens. Applicant further argues that “Jacek fails to teach, disclose, suggest or provide any guidance in arriving at SEQ ID NO: 1 as taught by Applicant” (page 15 para. 2). However, new grounds of rejection are set forth above, that rely on Mejan, who teaches SEQ ID NO: 1 (see rejection above). Applicant further argues that “[t]he Office admits that "Jacek fails to explicitly teach that the VlsE antigen from Borrelia burgdorferi, which contributes to Borrelia burgdorferi persistence, is 'microcolony persister form antigens'. Jacek also fails to explicitly teach diagnosing Lyme Disease/PTLDS". See, Office Action, pg. 15” (page 15 para. 2). However, Feng is relied upon for the deficiencies in Jacek argued by Applicant (see rejection above). Applicant further argues that “[n]either reference [Jacek and Feng] has identified the combination of MPAs and antibodies to the C6 SEQ ID NO: 1 peptide as taught by Applicant… Moreover neither reference discloses SEQ ID NO: I nor provide any guidance out of infinite possibilities to arrive at this sequence” (page 15 last paragraph and page 16 para. 1). However, the newly recited combination of MPAs and antibodies to the C6 SEQ ID NO: 1 peptide is addressed in the new grounds of rejection set forth above, i.e. in view of Jacek, Feng, Richards and Mejan (see rejection above). Applicant further argues that “Tate also fails to disclose the combination of MPAs and antibodies to the C6 SEQ ID NO: I peptide as taught by Applicant…Mejan also fails to disclose the combination of fails to disclose the combination of MPAs and antibodies to the C6 SEQ ID NO: 1 peptide as taught by Applicant” (page 16 para. 6 and page 17 para. 1). However, new grounds of rejection are set forth in view of Jacek, Feng, Richards and Mejan that address the combination of MPAs and antibodies to the C6 SEQ ID NO: 1 peptide (see rejection above). Applicant further argues that “[t]he Office admits that "Embers fails to teach wherein the antigens comprise microcolony persister form antigens (MPA)." See, Office Action, pg. 21. Jacek and Feng are cited in an attempt to remedy at least this deficiency of Embers. However, as discussed above Jacek and Feng fail to teach disclose or otherwise suggest the instantly claimed invention. Therefore, Embers in view of Jacek and Feng also fails to obviate the instantly claimed invention. However, to advance prosecution, Applicant has amended claim 21 in line with claims 1 and 11” (page 17 para. 5). However, new grounds of rejection are set forth above for claim 21 over Embers in view of Jacek, Feng and Mejan (see rejection above).
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FERNANDO IVICH whose telephone number is (703)756-5386. The examiner can normally be reached M-F 9:30-6:00 (E.T.).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory S. Emch can be reached at (571) 272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677