The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse of Group I, claims 1-4 and 8-10 in the reply filed on September 9, 2025 is acknowledged.
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.
Claims 1-4 and 8-10 are rejected under 35 U.S.C. 112(a), as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. Claim 1 is a method for detecting lupus anticoagulants in a reaction mixture prepared by combining a lupus anticoagulant-sensitive activate partial thromboplastin time reagent with a plasma sample, continuously measuring a measurement variable over time to obtain a function of time-dependent measurement values and determining a coagulation time for the reaction mixture. The claim also requires determining a maximum reaction velocity and/or a maximum reaction acceleration from the function of time-dependent measurement values, determining an absolute value of the difference (|DeltaS|) between a measurement value at a start of the continuous measurement and a second measurement value at and end of the measurement for the reaction mixture, using the |DeltaS| to determine a relative maximum reaction velocity and/or a relative maximum reaction acceleration based on claimed equations and detecting the presence of lupus anticoagulant if the relative maximum reaction velocity and/or relative maximum reaction acceleration are within a predetermined lupus anticoagulant-specific range. Relative to the above claim, relative to the state of the prior art Wands factor, steps (i), (ii) and (iii) are known based at least the newly cited Braun (see at least figure 1, table 1 and their associated discussion) and Shima (see at least figure 1, table S1 and their associated discussion) papers. In particular, the type of analysis described in the Shima paper is called clot waveform analysis (CWA). Table 1 of Braun shows that a value, delta, similar to the |DeltaS| (amplitude of the signal change) is also known. Thus these steps are not new. What is new is the determination of the relative maximum reaction velocity and/or relative maximum reaction acceleration and its used to detect lupus anticoagulant in the reaction mixture if they are within a predetermined lupus anticoagulant-specific range.
With respect to the breadth of the claims Wands factor, they cover the use of any APTT reagent that is lupus anticoagulant-sensitive. The second paragraph on page 5 of the instant specification teaches that a lupus anticoagulant-sensitive APTT reagent typically contains a reduced concentration of phospholipids, compared to a lupus anticoagulant-insensitive APTT reagent, meaning that measurement of the coagulation time of lupus anticoagulant-containing samples using such a reagent leads to a prolonged coagulation time, compared to normal (lupus anticoagulant-free) samples. Relative to the level of predictability Wands factor with this aspect of the claim, the paragraph bridging pages 503-504 of the newly cited Kumano paper teaches that most commercial APTT reagents are composed of activators, along with various phospholipids. However, the sensitivity and specificity of those reagents to heparin, LA, and coagulation deficiencies vary, because of differences in the activators employed, such as silica and ellagic acid, as well as the sources, properties, and total concentrations of phospholipids. These points have been well documented in past reports and it was considered that the usefulness of ICA for LA diagnosis is dependent on the APTT reagents used. In this respect, the first full paragraph on page 505 of the paper lists the APTT reagents used as Thrombocheck APTT-SLA, Actin FSL, APTT-SP and PTT-LA. For these reagents, the phospholipid source of their reagents were synthetic, rabbit including soybean, synthetic, and cephalin, respectively. The newly cited Cloherty paper studied a method reported to differentiate lupus anticoagulant caused prolongation of the APTT time using different APTT reagents. The three reagents are given on page 139: 1) a micronized silica-containing reagent (Automated APTT); 2) an ellagic acid-containing reagent (Actin FSL); and 3) a kaolin-containing reagent. Of note relative to the predictability of the art is the fact that only one of the three reagents gave results that were usable to detect Lupus anticoagulants by the reported method (see the discussion on page 140 of the reference). Thus the art recognizes that there is unpredictability associated with the usability of the APTT reagent based on the source and/or type of phospholipids and/or other components in the different commercial reagents.
The newly cited Moore paper is a review directed toward current controversies in lupus anticoagulant detection. In the introduction of the paper Moore teaches that that antiphospholipid syndrome (APS) is diagnosed when laboratory assays demonstrate the presence of persistent antiphospholipid antibodies (aPL) in patients presenting with thrombosis or pregnancy morbidity. Standardization difficulties for aPL assays persist, arising from issues such as antibody heterogeneity, reagent variability and differing interpretation strategies, and so generation of gold standard assays and reference plasmas remains elusive. The presence of LA is inferred based on antibody behavior in a medley of phospholipid-dependent coagulation assays. No single type of coagulation test is sensitive to all LA and two test systems of differing analytical principles should be employed to maximize detection rates. One of the problems with employing global coagulation assays to infer the presence of LA is that standard interpretation criteria necessarily assume that all else about the patient’s coagulation status is normal, so each test has significant potential for compromised specificity, particularly in situations of therapeutic anticoagulation. This adds a further layer of complexity to LA identification and several guidelines with broad but not complete agreement are available to guide best practices. The main interferences for each LA assay type are shown in Table 1. Of relevance to the instant claims are the interferences given for the intrinsic pathway based assays that include LA-responsive routine APTT and Dilute APTT. The Non-LA causes of screening test elevation are given as 1) deficiencies of factors II, V, VIII, IX, X, XI, XII, PK and/or HMWK; 2) reduced fibrinogen; 3) anticoagulation with VKA, UFH, (LMWH), DFXa and/or DTI; and 4) non-phospholipid-dependent inhibitors. The shortening of screening test causes are 1) elevated FVIII and/or FIX and 2) elevated fibrinogen. Since the claimed |DeltaS| parameter is affected by/correlated with the fibrinogen concentration and the APTT reagents are known to be affected by anticoagulants and/or many of the factors involved in the intrinsic coagulation pathways, the predictability of the assays for detecting lupus anticoagulants would also be expected to depend on these same interferences. In discussing which assays to use, the paragraph bridging pages 2-3 of the paper teaches that numerous assay types for LA detection have been proposed and used over the years and earlier guidelines more or less gave practitioners free reign over which, and how many, to use, albeit with acknowledgement that the pairing of dilute Russell’s viper venom time (dRVVT) and activated partial thromboplastin time (APTT) can achieve good detection rates. However, the most recent guideline from the International Society on Thrombosis and Haemostasis (ISTH), published in late 2009, suggests that that the risk of false-positive results is increased to unacceptable levels if more than two screening tests are performed and restricts assay choice to only dRVVT, for its specificity to clinically significant antibodies, and APTT with low phospholipid concentration because of its sensitivity. This recommendation has its basis in the considerable body of evidence indicating that the dRVVT and APTT pairing is diagnostically efficacious, and additionally, it serves to nurture common diagnostic practices. An important caveat here is that not all reagents from different manufacturers for the same test perform identically, particularly in the case of APTT, and reagents for LA detection must be chosen carefully. Many APTT reagents intended for routine coagulation screening to primarily detect coagulation factor deficiencies and monitor heparin therapy do not contain dilute phospholipid and/or a suitable phospholipid composition, compromising their responsiveness to LAs. Available routine APTT reagents span a continuum of low, intermediate and (relatively) high LA sensitivity, while other APTTs are specifically formulated only for use in LA detection (see the newly cited Fritsma paper). A valuable recommendation is made in the guideline from the Clinical and Laboratory Standards Institute (CLSI) from 2014 to employ a LA-insensitive APTT in routine coagulation screening and a separate, LA-sensitive reagent when specifically investigating for LA. This permits interpretation of LA assays themselves unencumbered by the possibility of many interfering factors if the routine APTT is normal. It has been suggested that ellagic acid-activated APTTs are less sensitive to LA and that only silica-activated reagents should be used. This is based on reports comparing routine APTT reagents employing different activators yet ellagic acid-activated APTTs that are LA-sensitive have been described and the low sensitivity in the other reagents is merely coincidental to their phospholipid composition. This paper’s teaching that reagents span a continuum of sensitivity to lupus anticoagulants brings into question the utility of a reagent that has intermediate sensitivity to lupus anticoagulants based on an example that used one with high sensitivity to lupus anticoagulants. It also reinforces other teachings that the reagent’s effectiveness may depend on the reagent composition.
The instant disclosure provides a single example showing differences in determined relative maximum reaction velocity and/or relative maximum reaction acceleration parameters for samples from two normal individuals, one sample having added low molecular weight heparin, one sample with unfractionated heparin, two factor VIII-deficient samples and 10 samples in which the dilute Russell’s viper venom test indicated the presence of lupus anticoagulant. Of note in this example is the fact that the highest value of the relative maximum reaction velocity and relative maximum reaction acceleration parameters is 2.3 while the lowest values for the heparin and factor VIII-deficient samples for these same parameters is 2.7. The newly cited de Pablo paper looked at the fibrin polymerization rate in patients with primary antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). The last full paragraph on page 1 of the instant specification attribute lupus anticoagulants as the cause of at least the antiphospholipid syndrome. The third full paragraph on page 222 of the paper teaches that they studied 39 patients with one or both of the two conditions and 31 age- and gender matched controls. Table 2 shows the measured results along with an error range resulting from a statistical analysis of the data. In the paragraph bridging the columns of page 224, a few limitations of the study are outlined. Relevant to the extent of experimentation needed to make or use the invention based on the content of the disclosure Wands factor, one of the limitations listed by de Pablo is the small number of patients and controls. Another limitation listed was that they did not investigate additional thrombogenic factors. With respect to these limitations, the newly cited Kumano paper evaluated the correlations of a parameter, the index of circulating anticoagulant (ICA), with INR, heparin concentration, and coagulation factor activity in samples from hemophilia patients using several different APTT reagents, and also investigated the effect of APTT-prolonged plasma on the ICA parameter. The first full paragraph on page 505 teaches that hemophilia A is associated with Factor VIII activity. The paragraph bridging pages 504-505 teaches that they studied samples from 28 LA-positive patients with various diseases, including antiphospholipid syndrome. In addition, they tested samples from 23 patients who received warfarin and 19 who received unfractionated heparin for dialysis, as well as from 29 hemophilia A patients, along with 61 healthy subjects with normal coagulation test results used as controls. The last paragraph on page 505 gives the APTT value results of the different groups for the different reagents tested. From these values, it is clear that the different reagents show differences in the results. In the paragraph bridging pages 506-507, the sensitivity and specificity of the ICA parameter for LA was described/discussed. In particular the sensitivity was similar for all the samples except the heparin samples. Based on their results, they concluded that the ICA parameter calculated from APTT clotting time was useful for LA diagnosis, because it could distinguish LA-positive samples from normal, warfarin, and hemophilia samples, but not heparin samples. Nevertheless, it was difficult to separate samples with low LA activity from LA negative samples and a clearer cut-off value was needed (see the discussion in the second full and last paragraphs on page 508 of the paper).
The newly cited Hoxha paper studied the interference of direct oral anticoagulants when measuring lupus anticoagulants (LAC) with reagents and recommended that it does not seem advisable to carry out LAC testing during anti-factor Xa and anti-factor IIa treatment because of the risk of false-positive results.
The newly cited Seheult paper investigated the effects of indirect- and direct-acting anticoagulants on the interpretation of lupus anticoagulant (LAC) assays. This analysis included 7,721 LAC panels. Direct oral anticoagulants, warfarin, and unfractionated heparin (UFH) were associated with higher LAC positivity rates compared with patients not receiving documented anticoagulation (83% for argatroban, 58% for dabigatran, 72% for rivaroxaban, 53% for apixaban, 56% for warfarin, and 36% for UFH vs 29% for no anticoagulation, P < .025). Direct thrombin inhibitors mainly affected the activated partial thromboplastin time–based assays and the tissue thromboplastin inhibition index (TTI), while direct factor Xa inhibitors mainly affected the TTI and the dilute Russell viper venom ratio. They concluded that results of LAC testing performed while patients are receiving anticoagulant therapies should be interpreted with caution to avoid misdiagnosing patients with the antiphospholipid syndrome and potentially committing them to long-term anticoagulation therapy. Again there is concern that anticoagulants will interfere with the diagnosis of lupus anticoagulants. This is a reflection on the predictability of the art Wands factor.
Based on the limited number of samples, especially for the heparin and Factor VIII-deficient groups of the instant example, it is difficult to say that there is a clear difference between the relative maximum reaction velocity and/or the relative maximum reaction acceleration values of the lupus anticoagulant samples and those same values measured for heparin and/or Factor VIII-deficient samples. This is particularly the case since it is difficult to tell whether the two values from the heparin and Factor VIII-deficient groups represent the full range of variability or only a portion of that range. Additionally, since there is a lack of information on the actual activity of the lupus anticoagulant samples, it is difficult to say whether the claimed relative maximum reaction velocity and/or the relative maximum reaction acceleration parameters are capable of separating samples with low LA activity from LA negative samples. Finally, based on the limited number of groups tested, it is not clear whether additional thrombogenic factors such as the administration of anticoagulants such as warfarin might present situations that the claimed separate samples with low LA activity from LA negative parameters would be unable to separate the LA samples from samples with other thrombogenic factors.
The paragraph bridging pages 1086-1087 of Braun teaches a linear relationship between the delta parameter and fibrinogen concentration with the effect on the APTT_delta by very low concentration of some factors and added heparin being unexpected observations. In the de Pablo paper Table 2 presents the fibrinogen concentration for the various conditions studied. Since it is correlated to the measured delta parameter, the fact that the systemic lupus erythematosus (SLE) group and the control group have a similar fibrinogen concentrations sows that there is a possibility that the claimed relative maximum reaction velocity and/or the relative maximum reaction acceleration parameters might vary depending on the type of lupus anticoagulants present in the sample. This is another factor relevant when considering the predictability Wands factor.
In the paragraph bridging pages 1417-1418 of the Shima paper, a recommended method for standardization of the CWA is presented. Of note and relevance to the instant claims is the teaching that APTT reagents used for the detection of anti-phospholipid antibodies are not recommended for the CWA because their sensitivity for assessing low clotting function is not sufficiently high. Her is more evidence that one of ordinary skill in the art would have questions regarding the predictability of the parameters used in the instantly claimed method.
Based on the lack of predictability of the APTT reagent response and the limited information given relative to the single example, there is a significant amount of experimentation that would be required to test sufficient samples to determine the ability of the claimed relative maximum reaction velocity and/or the relative maximum reaction acceleration parameters to actually detect the presence of lupus anticoagulants with a reasonable expectation of success. Thus the claims lack enablement.
Claims 1-4 and 8-10 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. In claim 1, “the coagulation time”, “the maximum reaction velocity”, “the maximum reaction acceleration”, “the absolute value”, “the difference”, “the relative maximum reaction velocity” and “the relative maximum reaction acceleration” do not have proper antecedent basis. With respect to the “lupus anticoagulant-sensitive activated partial thromboplastin time” reagent language of claim 1, the teaching in the paragraph bridging the columns of page 905 of the newly cited Fritsma paper that there are reagents with low, intermediate and high sensitivity to lupus anticoagulants, it is not clear if the language covers a reagent of intermediate sensitivity or if the language only covers the highly sensitive reagents. In other words, what if any is the distinction between a reagent that is lupus anticoagulant-sensitive and one that is not? In claims 3 and 4 “the maximum” and “the minimum” do not have proper antecedent basis.
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 and 8-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claim(s) recite(s) a correlation between the maximum reaction velocity (vmax) and/or the maximum reaction acceleration (amax) of a function S(t) representing the continuous measurement of a variable S in a reaction mixture of a plasma sample with a lupus anticoagulant-sensitive activated partial thromboplastin time (APTT) reagent and the presence of lupus anticoagulants in the plasma sample using one of the following mathematical equations to represent the correlation: vmax rel = vmax/|DeltaS| and amax rel = amax/|DeltaS|, respectively. This judicial exception is not integrated into a practical application because as explained above the additional steps do not add a meaningful limitation to the method amounting to insignificant extra-solution activity. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional steps related to creating of the reaction mixture, gathering the data on variable S that forms the function S(t) and determining DeltaS, vmax and amax are known data gathering steps as shown by the disclosure found at least in the newly cited Braun and Shima papers so that the invention is little more than the correlation represented by the above equations.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The additionally cited art is related to measuring lupus anticoagulants, methods in which a variable of a coagulation reaction is continuously measured and analyzed using clot waveform analysis and potential compounds that interfere with the measurement of lupus anticoagulants using the APTT reagent.
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/ARLEN SODERQUIST/Primary Examiner, Art Unit 1797