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 this Action, the references to the instant specification refer to the Pre-Grant Publication of the instant application (US 2023/0324382 A1).
Claim Status
The claim set filed on 31 January 2023 contains claims 1-20, which are currently pending.
Election/Restrictions
Applicant’s election of Group I (claims 1-16) in the reply filed on 26 September 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 17-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 26 September 2025. Thus, claims 1-16 will be examined on the merits herein.
Priority
The instant application claims priority to U.S. Provisional Application 63/267,412 (filed 1 February 2022). Therefore, the effective filing date of instant claims 1-16 is 1 February 2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8 August 2023 are both in compliance with the provisions of 37 CFR 1.97. Accordingly, each information disclosure statement is being considered by the examiner.
Drawings
The drawings filed on 28 June 2023 are objected to because of the following:
In FIG. 16A, the figure shows a heat map, but the details cannot be differentiated in the black and white drawings;
There are no figures labelled “23A” and “23B”, but there are two of each of “24A” and 24B”; and
In all figures labelled “24A” and “24B”, it is difficult to differentiate which bars correspond to the group noted in the legend in the black and white drawings (see Examiner’s view below). Additionally, the second set of FIG. 24A-B (i.e., the bottom figures in the Examiner’s view below) do not have a label on the y-axis (including units being measured).
PNG
media_image1.png
680
840
media_image1.png
Greyscale
PNG
media_image2.png
593
618
media_image2.png
Greyscale
PNG
media_image3.png
720
897
media_image3.png
Greyscale
PNG
media_image4.png
712
756
media_image4.png
Greyscale
Examiner’s view of all figures labelled “24A” and “24B”. Note that the bars are in shades of grey, making it difficult to identify which bars correspond to the color noted in the legend.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
If Applicant wishes to provide color photographs and/or drawings, note that color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claim 1 is objected to because of the following informalities: in claim 1, there should be an “and” between steps (e) and (f). Appropriate correction is required.
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 6-7, 10, and 14-15 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 6 recites, “wherein the subject has exhibited the symptom for one month or less.” It is unclear what reference point is used to measure “one month or less” (e.g., from the time of testing, from the time of obtaining the sample, etc.). In the interest of compact prosecution, the limitation has been interpreted to mean “exhibited the symptom for one month or less at the time that the claimed method is performed.”
Claim 6, which depends upon claim 5, recites the limitation "the symptom". There is insufficient antecedent basis for this limitation in claim 6 (which recites “one or more… symptoms”) or the claim(s) from which it depends.
Claim 7 recites, “wherein the subject is asymptomatic for Lyme disease, but may have come in contact with a blacklegged tick selected from Ixodes scapularis and Ixodes pacificus, and wherein the possible contact was within 1 month.” The term “contact” is not defined in that specification, so one of ordinary skill in the art would not be able to determine the scope of the claim because it is unclear what constitutes “contact” with the blacklegged tick species (Does being in a certain geographic area with the tick constitute contact? Does the tick have to touch or bite the skin of the subject?) Regarding the phrase “the possible contact was within 1 month”, it is unclear what reference point used to measure one month (e.g., within 1 month of the preforming the method of claim 1, within 1 month of obtaining the sample from the subject, etc.). In the interest of compact prosecution, the interpretation of “contact” will be explained in any rejections of claim 7.
Claim 8, which is dependent upon claim 1, recites, “wherein the lipid panel comprises one or more lipids selected from ceramide, sphingomyelin, hexosyl cholesterol, acyl hexosyl cholesterol, galactosyldiacylglycerol, and phosphatidylethanolamine.” However, the “lipid panel” is defined in claim 1 as “comprising at least the following lipids: phosphatidic acid (PA), phosphatidyl choline (PC), and phosphatidylserine (PS)”. Because claim 8 says that the lipid panel “comprises” and not “further comprises”, it is unclear what lipids must be present in the method of claim 8, and it is unclear if there is antecedent basis for “the lipid panel” of claim 8 in claim 1, or if the lipid panel of claim 8 is intended to be a different lipid panel. In the interest of compact prosecution, the claim has been interpreted to recite a lipid panel comprising phosphatidic acid (PA), phosphatidyl choline (PC), and phosphatidylserine (PS) and further comprising come or more of ceramide, sphingomyelin, hexosyl cholesterol, acyl hexosyl cholesterol, galactosyldiacylglycerol, and phosphatidylethanolamine, as is supported in at least para. 6-7 of the instant specification.
Claims 10 and 14 each recite, “wherein the subject has been exposed to a Lyme disease pathogen for one week or less.” It is unclear what reference point is used to measure “one week or less” (e.g., from the time of testing, from the time of obtaining the sample, etc.). Additionally, the phrase “exposed to a Lyme disease pathogen” is not defined in the instant specification. Thus, one of ordinary skill in the art cannot determine what is encompassed by “exposure” and would not be able to determine the scope of the claim. Furthermore, without a definition of what is meant by “exposure,” one would not be able to determine whether the exposure has happened. In the interest of compact prosecution, the interpretation of “exposure” will be explained in any rejections of claims 10 and 14.
Claim 15, which is dependent upon claim 13, recites the limitation "the panel" in line 2. There is insufficient antecedent basis for this limitation in the claim or the claim from which it depends.
Clarification is requested.
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 1, 11-13, and 15-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the method steps recited in claims 1 and 13, as written, does not reasonably provide enablement for methods comprising the steps recited in claims 1 and 13 and further comprising a step wherein if the measured level is greater than the predetermined value for at least one of the lipids in the panel, the subject is diagnosed as positive for Lyme disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the method of the invention commensurate in scope with these claims.
The focus of the enablement inquiry is whether everything within the scope of the claim(s) is/are enabled, at the time of filing, without requiring undue experimentation to make or use the invention. The factors to be considered in determining whether a disclosure would require undue experimentation include: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims: With respect to claim breadth, the standard under 35 U.S.C. §112(a) or 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole.
Claims 11 and 15 (which depend upon claims 1 and 13 and upon which claims 12 and 16 depend, respectively) each recite, “wherein if the measured level is greater than the predetermined value for at least one of the lipids in the panel, the subject is diagnosed as positive for Lyme disease.” The broadest reasonable interpretation of this limitation is that a positive diagnosis for Lyme disease occurs when the measured level antibodies against at least one of the lipids is greater than any possible predetermined value, which may not be constant.
The state of the prior art and the level of predictability in the art: There are several methods of diagnostic testing for Lyme disease known in the art. John and Taege (2019, Cleve. Clin. J. Med.; herein “John”) teach direct methods, Borrelia culture and PCR, and indirect methods, immunofluorescent assay, ELISA, and Western blot (pg. 754, Table 2). The indirect methods detect antibodies targeting Borrelia burgdorferi proteins including flagellin, outer surface protein C (OspC), and VisE (pg. 755, left col., para. 1). While determining and analyzing the levels of antiphospholipid antibodies in subjects, including those previously diagnosed with Lyme disease, is known in the art (Greco Jr., et al., 2011, Lupus; cited in IDS; herein “Greco”), antiphospholipid antibody titers has not been used in diagnosis of Lyme disease before the effective filing date of the claimed invention, and there is little data in the art regarding the levels of antibodies against the claimed lipids (anti-PC, PA, and PS antibodies) in subjects with Lyme disease. Based on the prior art, one of ordinary skill in the art would not be able to predict the appropriate predetermined value of a given antiphospholipid antibody necessary to diagnose a subject with Lyme disease.
The amount of direction provided by the inventor and the existence of working examples: The instant specification teaches that the “predetermined” or “cut-off” value used in the claimed method is “a dividing point for a quantitative result of a diagnostic test or screen to be indicative of a positive or negative result based on measurements of the level of a molecular marker(s).” (para. 84) Additionally, “the predetermined value or control value is a cutoff value based on a naïve control antibody level, either measured independently or measured using the same sample” (para. 95) In an example, the cutoff value (for each of the anti-PC, PA, and PS antibodies) is the “mean [of each antibody level] of the naïve controls plus 2.291 SDs” (para. 95 and 178). The data clearly show that immunologically naïve subjects have detectable levels of anti-phospholipid antibodies (Figure 15), so depending on the choice of the pre-determined level, these subjects could be improperly diagnosed as having Lyme disease. Also, the data show that the anti-phospholipid antibodies are relatively similar between the groups (Figure 15), so choosing a pre-determined level that is too high would result in many or all Lyme disease patients being improperly classified as not having Lyme disease. However, the instant specification does not provide the actual cutoff value for each antibody; FIG. 15 the control values are normalized to correspond to 1, with the cutoff values (+2.291 SD) marked by a dashed line (para. 28). Based on this, there is a particular value for each antibody level necessary to correctly diagnose Lyme disease, but the specification does not provide the values. Therefore, what is enabled by the instant specification and working examples is narrow in comparison to the scope of the claims, and the specification does not provide enough information with which one may overcome the known unpredictability in the art.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004)). The instant specification is not enabling for the claimed invention because one cannot follow the guidance presented therein, or within the art at the time of filing, and perform the claimed method without first making a substantial inventive contribution.
The claims recite the use of any generic “pre-determined value” to determine Lyme disease diagnosis, but the specification specifically demonstrates that not all values will result in a useful and accurate method. In order to perform the claimed method commensurate in scope with what is claimed, one of ordinary skill in the art would need to modify the method taught in the specification and the teachings of the art in order to perform the method of claims 1, 11-13, and 15-16 using any cutoff value to diagnose a subject as positive with Lyme disease. To do so would be going beyond what is considered “routine” in the art because the specification teaches that any cutoff value may be used to diagnose Lyme disease and the art does not provide guidance otherwise. Therefore, claims 11 and 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for failing to meet the enablement requirement.
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 1-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Claims 1 and 13 each recite steps of “detecting” the detectable binding agent or the bound antibodies, “measuring the level of antibodies”, and “comparing the measured levels…to a predetermined value.” The broadest reasonable interpretation of the term “detecting” encompasses mental processes, such as seeing or observing (see MPEP 2106.04(a)), as is evidenced by an example in the instant specification, which states, “By way of example, but not by way of limitations, a detectable binding agent may comprise an antibody linked to an enzyme, such as horseradish peroxidase (HRP). Addition of an HRP substrate, under enzymatic reaction conditions, will allow detection of the HRP-bound molecule and the target.” (para. 75) When HRP is bound by a substrate, a color change may be visible to the human eye.
Based on the above example, the step of “measuring the level of antibodies” may encompass evaluating or judging the intensity of the color change in order to determine the relative antibody levels in a sample. Thus, the full scope of “measuring” encompasses mental processes.
The action of “comparing the measured levels” involves evaluating data and falls within the category of a mental process and also is a mathematical calculation (i.e., abstract ideas).
Claims 11 and 15 each recite, “wherein if the measured level is greater than the predetermined value for at least one of the lipids in the panel, the subject is diagnosed as positive for Lyme disease.” This step recites a mental process (i.e., an abstract idea) and also a mathematical calculation of evaluating data in order make a diagnosis.
Claims 12 and 16 (which are dependent upon claims 11 and 15, respectively) each recite, “further comprising treating the subject for Lyme disease.”
This judicial exception is not integrated into a practical application because the application or use of the judicial exception does not go beyond generally linking the use of the judicial exception (i.e., “detecting” a binding agent or bound antibodies, “measuring the level of antibodies” and “comparing the measured levels”) to a particular technological environment or field of use. In this case, the recited steps of contacting an antibody-containing sample with lipids, incubating, and contacting antibodies with a detectable binding agent are performed in order to gather data for the steps of “detecting”, “measuring”, and “comparing” and are necessary precursors for all uses of these steps. Thus, steps (a)-(c) are extra-solution activity, and does not integrate the judicial exception into a practical application. See MPEP 2106.04(d)(2). An example of data gathering that the courts have found to be insignificant extra-solution activity include determining the level of a biomarker in blood, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968, as well as performing clinical tests on individuals to obtain input for an equation (In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989)). See MPEP 2106.05(g). An example of limitations that the courts have described as merely indicating a field of use or technological environment in which to apply a judicial exception include, for example, language informing doctors to apply a law of nature (linkage disequilibrium) for purposes of detecting a genetic polymorphism, because this language merely informs the relevant audience that the law of nature can be used in this manner (Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1379, 118 USPQ2d 1541, 1549 (Fed. Cir. 2016)). See MPEP 2016.05(h). Furthermore, the judicial exception is not integrated into a practical application because the claim does not recite additional elements that apply or use the judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition.
Claims 12 and 16 (which are dependent upon claims 11 and 15, respectively) each recite, “further comprising treating the subject for Lyme disease.” These claims do not integrate the judicial exception into a practical application because this limitation is not specific enough to effect a particular treatment or prophylaxis (MPEP 2106.04(d)(2)). In order to integrate the judicial exception(s) into a practical application, the treatment or prophylaxis limitation must be “particular,” i.e., specifically identified so that it does not encompass all application(s) of the judicial exception(s). In this case, the step of “treating the subject for Lyme disease is not particular and is merely instructions to “apply” the judicial exception(s) in a generic way. See MPEP 2106.04(d)(2). Additionally, limitations that the courts have described as merely indicating a field of use or technological environment in which to apply a judicial exception include, for example, a step of administering a drug providing 6-thioguanine to patients with an immune-mediated gastrointestinal disorder, because limiting drug administration to this patient population did no more than simply refer to the relevant pre-existing audience of doctors who used thiopurine drugs to treat patients suffering from autoimmune disorders, Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 78, 101 USPQ2d 1961, 1968 (2012). See MPEP 2106.05(h). Thus, the limitation does not integrate the judicial exception into a practical application because the application or use of the judicial exception does not go beyond generally linking the use of the judicial exception to a field of use.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional steps of contacting an antibody-containing sample with lipids, incubating, and contacting antibodies with a detectable binding agent are extra-solution activity of preparing for and gathering data for the steps of “detecting”, “measuring”, and “comparing” as discussed above. Additionally, the additional limitations only generally link the judicial exception to a particular field of use for the reasons described above. See MPEP 2106.05.
Regarding claims 2-10 (which depend upon claim 1) and claim 14 (which depends upon claim 13), each of these claims limits the additional elements of claim 1 or 13 (such as limiting the sample, subject, lipid panel, etc.) that are extra-solution activity, as described above. Thus, these claims do not integrate the judicial exception into a practical application or amount to significantly more than the judicial exception.
Therefore, claims 1-16 do not qualify as eligible subject matter (see MPEP 2106).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 8-9, and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Thorpe et al. (US 2016/0015826 A1; cited in IDS; herein “Thorpe”).
Regarding claims 1, 3, and 13, Thorpe teaches a method for enzyme-linked immunosorbent assay (ELISA) using a 96-well plate (i.e., a solid support) coated with at least phosphatidylserine (PS), phosphatidic acid (PA), and phosphatidylcholine (PC) (para. 712 and 714). The process of coating the plate comprises diluting the antibodies in n-hexane, adding the mixture to each well and allowing it to evaporate, followed by adding a blocking buffer to the wells (i.e., when added to the plate, the sample contacts a reagent composition comprising the lipids) (para. 712). Thorpe teaches that the method comprises: contacting the antiphospholipid antibody-containing test sample (i.e., the primary antibody), derived from mice (para. 706), to the coated plate and incubating for two hours (para. 711-712); contacting the bound antibodies with a secondary antibody, anti-mouse IgG-HRP (horseradish peroxidase; a detectable binding agent) (para. 711-712); adding a developing solution comprising H2O2, thereby detecting the bound IgG-HRP (para. 711-712); measuring the level of antibodies by reading the optical density (OD) of samples (para. 712); and comparing the measurements to predetermined affinities of the antibodies to the phospholipids (para. 713-714 and Tables 3-4).
Regarding claim 2, Thorpe teaches that the sample is a serum sample (para. 696).
Regarding claim 8, Thorpe teaches that the plate may also be coated with phosphatidylethanolamine (PE) and sphingomyelin (para. 714).
Regarding claim 9, Thorpe teaches that the subjects from which the immune sera (sample) was obtained were BALB/c mice (para. 693-694 and 696). There is no evidence that these mice have been treated for Lyme disease and one of ordinary skill in the art would expect that BALB/c mice used to generate antibodies would not have been exposed to or come into contact with tick carrying a Lyme disease pathogen.
Claim Rejections - 35 USC § 103
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The 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, 8-9, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Thorpe (US 2016/0015826 A1; cited in IDS) in view of Louisville APL Diagnostics, Inc. (2020, “APhL ELISA® IgG HRP Kit”; herein “APL”).
The teachings of Thorpe with respect to claims 1-3, 8-9, and 13 are set forth in the 102 rejection above (para. 45-47).
Regarding claim 4, Thorpe teaches that human Fc regions may be used in any phosphatidylserine binding protein (e.g., anti-phosphatidylserine antibody) (para. 42) and that the secondary antibody (i.e., detectable binding agent) may be another appropriate secondary antibody (para. 712), such as an anti-human secondary antibody which binds a human Fc region of an anti-phosphatidylserine antibody.
However, Thorpe does not explicitly teach a human subject or a detectable binding agent comprising anti-human IgG comprising a detectable label, as in claim 4.
Regarding claims 1-4 and 13, APL teaches a method for detecting and measuring IgG antiphospholipid antibody levels in human serum or plasma (section 1) comprising: incubating sera or plasma in ELISA strips coated with the APhL ELISA® Phospholipid Antigen (section 6.2(d)), which is a combination of phosphatidylserine (PS), phosphatidic acid (PA), and β2Glycoprotein I (section 2, para. 2); adding to the ELISA strip APhL ELISA® HRP IgG Conjugate (section 6.2(f)), which comprises anti-human IgG antibodies labeled with horseradish peroxidase (section 3); detecting bound antibodies by adding TMB to the mixture to cause a color change (sections 3 and 6.2(g)); and measuring antibody levels by colorimetric detection in a microplate reader (sections 3 and 6.2(h)).
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to modify the method of Thorpe by performing the method on human serum or plasma (which will contain human antibodies) and using anti-human IgG antibodies labeled with horseradish peroxidase, as taught by APL, thereby arriving at the invention of claims 1-4, 8, and 13. The person of ordinary skill in the art would have been motivated to make the modification because the using anti-human IgG antibodies to bind antiphospholipid antibodies in a sample allows for the detection method to be used on samples from humans, as is taught by APL, and doing so in the method of Thorpe would allow for the detection of the full range of antiphospholipid antibodies taught in Thorpe in human samples. Therefore, the combination is also desirable (see MPEP 2144(II)). The person of ordinary skill in the art would have had a reasonable expectation of success because Thorpe teaches that their ELISA method may be used with any appropriate secondary antibody and APL teaches that antiphospholipid antibodies may be detected in human serum or plasma using anti-human IgG antibodies. Therefore, the combination leads to expected results because each element performs the same function as is does individually.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, all elements (i.e., ELISA plate or test strip coated in phospholipids, secondary antibody with a detectable label, plasma, serum, human subject, and anti-human IgG with a detectable label) were known in the art. In addition, combining these elements yields a method/composition wherein each element merely performs the same function as it does separately; thus, the results of the combination would be recognized as predictable to one of ordinary skill in the art. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claims 1-10 and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Thorpe (US 2016/0015826 A1; cited in IDS) in view of APL (2020, “APhL ELISA® IgG HRP Kit”) and further in view of John (2019, Cleve. Clin. J. Med.) and Kerstholt et al. (2020, Ticks Tick Borne Dis.; herein “Kerstholt”).
The teachings of Thorpe with respect to claims 1-3, 8-9, and 13 are set forth in the 102 rejection above (para. 45-48), and the teachings of Thorpe with respect to claim 4 is set forth in the 103 rejection above (para. 53).
Additionally, Thorpe teaches that therapeutic conjugates of their phosphatidylserine binding constructs may be used to treat Lyme disease (para. 632). Thorpe also teaches diagnostic kits that may include labelled antibodies that bind to PS or any other agent suitable for diagnosing the disease to be treated, such as Lyme disease (para. 489).
The teachings APL with respect to claims 1-4 and 13 are set forth in the 103 rejection above (para. 55).
However, neither Thorpe or APL teach a subject that tests positive for Lyme disease in standard two-tier test (STT) and/or exhibits one or more of the symptoms described in claim 5, a subject exhibiting a symptom of Lyme disease for one month or less, as in claim 6, a subject asymptomatic for Lyme disease, as in claim 7, or a subject exposed to a Lyme disease pathogen for one week or less, as in claims 10 and 14.
Regarding claims 5 and 7, John teaches that 85% of Lyme disease patients infected with B. burgdorferi exhibit the erythema migrans rash, which occurs between 3 and 30 days of a tick bite (pg. 752, left col., para. 3). John teaches that infection by B. burgdorferi is transmitted by bites from ticks (Ixodes scapularis and Ixodes pacificus), i.e., direct physical contact between the tick and subject (pg. 751, right col., para. 4 and pg. 752, left col., para. 3).
Regarding claim 6, John teaches that, as of publication in 2019, there was no recommended testing regimen during the first 4 weeks of disease, because of the limited number of antigens expressed by B. burgdorferi in the early stage of infection (Table 5 and pg. 755, right col., para. 2 – pg. 756, left col., para. 3).
Regarding claims 10 and 14, John teaches that antibody levels against B. burgdorferi protein antigens Fla, OspC, and VisE-IR6 (pg. 755, left col., para. 1) remain below detection limits during the first week after exposure to B. burgdorferi, which is transmitted in only 5% of bites by infected ticks (pg. 752, left col., para. 3-4).
Kerstholt teaches that B. burgdorferi, the causative agent of Lyme disease, contains only two phospholipids in its membrane, phosphatidylglycerol (PG) and phosphatidylcholine (PC), and that it requires exogenous choline in order to produce these lipids (section 2.2.2.1, para. 1 and section 2.2.2.2, para. 1). Kerstholt teaches that B. burgdorferi may obtain exogenous choline by breaking down host membrane lipids, producing lipid mediators that can play a role in inflammatory activation and immune response, and that host-membrane-derived phospholipid metabolites (e.g., phosphatidylcholine made from choline derived from host membranes) may be useful diagnostic markers for early stages of Lyme disease (section 2.2.2.2).
Therefore, it would have been prima facie obvious, before the effective filing date of the claimed invention, to a person of ordinary skill in the art, to further modify the method of Thorpe and APL by using samples derived from human subjects that have exhibited Lyme disease symptoms for less than a month, are asymptomatic for Lyme disease, and/or have been exposed to a Lyme disease pathogen for less than a week, as taught by John, thereby arriving at the invention of claims 1-3, 5-8, 10, and 13-14. The person of ordinary skill in the art would have been motivated to make the modification because John teaches that serological testing for antibodies against protein antigens are not always reliable during early stages of Lyme disease, and Kerstholt suggests that B. burdorferi breaks down host membrane lipids as a part of its normal metabolism, thereby activating the host immune response against host-membrane phospholipids (section 2.2.2.2). Thus, the detection of antiphospholipid antibodies may be useful in the early detection of Lyme disease. Therefore, the combination is also desirable (see MPEP 2144(II)). The person of ordinary skill in the art would have had a reasonable expectation of success because the subject population described by John is known to contain antibodies against phospholipids, so samples from that population would contain antibodies to be detected by the method of Thorpe, and the method of Thorpe is known to successfully detect phospholipids. Therefore, the combination leads to expected results because each element performs the same function as is does individually.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that combining prior art elements according to known methods to yield predictable results, is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. In the instant case, all elements (i.e., method for detecting antiphospholipid antibodies, that have exhibited Lyme disease symptoms for less than a month, are asymptomatic for Lyme disease, and/or have been exposed to a Lyme disease pathogen for less than a week) were known in the art. In addition, combining these elements yields a method/composition wherein each element merely performs the same function as it does separately; thus, the results of the combination would be recognized as predictable to one of ordinary skill in the art. Therefore, the claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY M MORGAN whose telephone number is (703)756-5388. The examiner can normally be reached M-F 9-5 ET.
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, VANESSA FORD can be reached at 571-272-0857. 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.
/BAILEY M MORGAN/
Examiner, Art Unit 1645
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674