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 .
Status of the Claims
Claims 1, 3-6, 8, 11, 13, 16, 19, 25, 35-36, 39-40, 46, and 58-59 are pending in the application and are the subject of this office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4 September 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Interpretation
It is noted that the claims recite the term “dIgA” which is defined in the specification as follows:
Pg. 10, Ln. 21-24: the term “dIgA” as used herein refers to dimeric or higher polymeric forms of IgA which are bound together by a IgA J-chain.
Such that “dIgA” in the instant application is not limited to specifically dimeric IgA but also includes polymeric IgA.
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, 3-6, 8, 11, 13, 16, 19, 25, 35-36, 39-40, 46, and 58-59 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of an application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
Further, to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include: a) the scope of the invention; b) actual reduction to practice; c) disclosure of drawings or structural chemical formulas; d) relevant identifying characteristics including complete structure, partial structure, physical and/or chemical properties, and structure/function correlation; e) method of making the claimed compounds; f) level of skill and knowledge in the art; and g) predictability in the art.
Claim 1 and its dependents are directed to “a method for detecting gut barrier dysfunction and/or cirrhosis in a subject”. The method steps of claim 1 include either: determining the ratio of dIgA and mIgA in a sample and comparing the ratio to a threshold; or determining the ratio of dIgA1 or dIgA2 or mIgA1 or mIgA2 and comparing the ratio to a threshold.
Claims 3-5, 16 further limit the relevant ratio and threshold used in the method.
Claim 6 indicates specific numeric indications for the threshold value.
Claims 8, 11, 13, 19 further limit reagents and methods used for detection of different IgA levels in the sample.
Claims 25 and 39-40 further limits the subject and sample type used in the method.
Claims 35-36, and 58-59 further describe the test strip of the method.
Claim 46 adds a treatment step to the method.
However, even in light of these limitations, what is disclosed by the application as originally filed is inadequate to prove possession of the full scope of the claimed invention at the time of filing for either the independent claim or any of the dependent claims.
Reduction to practice provided in the specification is unique to a specific lateral flow test strip which is produced with particular concentrations of capture reagent at three different test lines which are arranged in a particular order and which comprises the use of particular species of labels (see examples 2 and 3; e.g. Pg. 29-30: the first test line contains 1 mg/ml of the recombinant protein, chimeric secretory component and forms a pIgR-dIgA complex on the test strip when reacted with sample. The second test line contains 0.25 mg/ml of anti-human IgA2 monoclonal antibody which forms an anti-IgA2-IgA2 complex on the test strip when reacted with sample. The third test line is 0.025 mg/ml recombinant protein L which forms a protein L:monomeric IgA complex when reacted with sample. Notably protein L also binds both IgG and IgM antibody isotypes, and so the amount of monomeric IgA bound represents the relative level of IgA compared to other isotypes as well as the absolute amount of monomeric IgA.). The specification indicates that the threshold ratio of dIgA:mIgA used for determination of gut barrier dysfunction and/or cirrhosis is calculated as shown in Figure 6, wherein Figure 6 indicates that the threshold/ratio is a ratio of arbitrary units from detection of IgA on the specifically described lateral flow test strip as detected by a specific reader (Pg. 30, Ln. 23: Axxin AX-2X reader). All numerical data and reduction to practice provided in the specification appears to be based off results measured in arbitrary units on the specifically described lateral flow device.
The specification does not provide support or reduction to practice of any other method using any other device or variation of the device, and does not provide calculations or data which would allow one of ordinary skill in the art to convert the ratios and thresholds calculated with arbitrary units from this specific device into different units which would be transferrable and reproducible for other methods of IgA detection (i.e. there is no data which indicates how arbitrary units are related to actual concentrations). That is, for example, claim 6 sets forth specific numeric thresholds for the ratio of dIgA:mIgA used to detect gut barrier dysfunction and/or cirrhosis, but these ratios are specific to the arbitrary units yielded by the specifically described lateral flow device, and it is not clear how those ratios would be conserved and/or converted to be useful in any other embodiment encompassed by the claims which comprises a different means or device for detection of IgA subtypes and conformations.
Even in light of the amendments to the claims which require contacting the sample with binding agents disposed on a test strip, the limitations provided by the claims are still much broader than what is disclosed by the specification. That is, the specification discloses one particular lateral flow test strip with particular concentrations of three particular capture reagents in a particular order, comprising the use of particular labels but the claims do not include these particular details or limitations.
Further, the claims encompass a second embodiment set forth by claim 1: “determining the dIgA1 or dIgA2 level and mIgA1 or mIgA2 level in a biological sample from the subject and a ratio thereof and comparing the ratio to a threshold” which, by its broadest reasonable interpretation appears to encompass the alternative use of four different ratios (and their inverses): dIgA1:mIgA1, dIgA2:mIgA2, dIgA1:mIgA2, or dIgA2:mIgA1. However, the specification does not provide reduction to practice or specific examples of any of these embodiments, and does not identify any particular ratio or threshold of these components which is shown to be useful in determining gut barrier dysfunction and/or cirrhosis. The only relevant data and reduction to practice provided by the specification is measurement of total IgA2 and measurement of dIgA1 and dIgA2. No examples or reduction to practice are provided to support measurement of mIgA1 or mIgA2 or use of such measurements in determining gut barrier dysfunction and/or cirrhosis.
Predictability in the art is low for a number of reasons. All claims with the exception of claim 25 encompass the use of any sample type in the method, but reduction to practice is provided only for plasma samples (see Examples 2 and 3), and levels of IgA and its different subtypes and conformations vary between different sample types, such that one of ordinary skill in the art would not predictably expect to see the same trends, ratios, and levels of total IgA or IgA conformations and subtypes in different sample types (see, e.g. Delacroix et al (IgA subclasses in various secretions and in serum. Immunology. 1982 Oct;47(2):383-5.); previously cited).
The prior art does not provide teachings for the comparison of ratios of dIgA1:mIgA1, dIgA2:mIgA2, dIgA1:mIgA2, or dIgA2:mIgA1 to any particular threshold for the detection or diagnosis of gut barrier dysfunction and/or cirrhosis.
Predictability is low even when limited to detection on a lateral flow device or test strip as in the amended claims. For example, a lateral flow device which meets all the limitations of the instant independent claim could still be expected to yield different results from the lateral flow device disclosed and supported by the specification. For example, variation in the detection label used, the reader used, the capture reagents used, the order of capture reagents used, and the total and relative concentration of each capture reagent used would be expected to produce variation in the arbitrary units detected at each test line and in the ratio of signal produced at each test line (for the same sample). It is not clear how or whether the ratios and thresholds calculated in the instant specification would translate or be conserved across different methods of detection of IgA, but one of ordinary skill in the art would not reasonably or predictably expect the ratio to necessarily be the same as what is demonstrated in the specification based off readings of arbitrary units from one particular device used with one particular reader.
In summary, the claims lack sufficient written description because the breadth of the claims is broad while the disclosure and reduction to practice provided by the instant specification is very narrow and is limited to a single embodiment whose results are particular to arbitrary units produced by a specific device and detected by a specific reader.
For all these reasons, the specification fails to provide adequate written description for the genera encompassed by the claim and does not reasonably convey to one skilled in the relevant art that the inventor(s) at the time the application was filed, had possession of the claimed invention.
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.
Claim 16 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 16 is rejected as indefinite because the criteria required to meet condition (i) are unclear. That is, condition (i) recites a number of different ratios and relationships between IgA conformations and subtyped, wherein the list is not joined by any particular conjunctions or requirements which indicate whether the condition is met when any single one of these criteria is met or whether the condition is met only when ALL of the criteria of condition (i) are met. In order to give the claim its broadest reasonable interpretation, it is interpreted herein that condition (i) and claim 16 is met when any single criteria set forth in part (i) is met. Clarification is required.
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, 3-6, 8, 11, 16, 19, 25, 35-36, 39-40, 46, and 58 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
The claims are directed to a method for detecting gut barrier dysfunction and/or cirrhosis in a subject by comparing ratios of different conformations and/or subtypes of IgA measured in the sample. Thus, the claims recite both a naturally occurring phenomena (i.e. the relationship between particular IgA ratios and particular disease states) and a mental step/abstract idea (i.e. wherein recitation of “detecting” a disease in a subject implies drawing a mental/diagnostic conclusion based off the gathered data).
The judicial exceptions are not integrated into a practical application because the claims as a whole are directed to the judicial exception itself. That is, the method and its limitations are directed to the judicial exception of detecting disease, and all actively recited method steps are necessary data gathering steps performed in support of the judicial exception. Additional limitations provided in the dependent claims limit particular reagents used in the method, specify the disease that is detected, or further limit the threshold to which the determined ratio is compared, but do not set forth limitations which integrate the judicial exceptions into a practical application.
Claim 46 recites a treatment step, however this treatment step is not sufficient to integrate the judicial exceptions into a practical application because the administration step is not particular and is instead merely instructions to apply the judicial exception in a generic way (i.e. the treatment step does not identify a single particular disease, specific patient population, type of treatment, or method of treatment administration, etc. and instead simply comprises an instruction to administer a treatment for the identified disease). See MPEP 2106.04(d)(2).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions. The method steps and limitations recited in both the independent and dependent claims do not amount to significantly more than the judicial exception because they pertain to necessary data gathering activities required for implementing the judicial exceptions. That is, a practitioner must measure and determine levels and ratios of IgA conformations and subtypes in order to be able to compare them to a threshold and draw a diagnostic conclusion (i.e. use the naturally occurring relationship between different IgA levels and ratios in order to perform the mental step of diagnosing or “detecting” a disease state). Steps which amount to data gathering in conjunction with a judicial exception are considered to be adding insignificant extra-solution activity to the judicial exception, and are not considered enough to qualify as significantly more when recited in a claim with a judicial exception. See MPEP 2106.05(g).
Further, the limitations of the claims beyond the judicial exceptions themselves are known to be routine and conventional in the art. That is, additional limitations are related to the detection of mIgA and dIgA (and/or other IgA subtypes) and particular methods of performing that detection in a biological sample. Wherein detection of IgA and its different conformations and subtypes (specifically including measurement via a test strip) is known in the art, as evidenced by the teachings of Delacroix et al ((1983) “Changes in Size, Subclass, and Metabolic Properties of Serum Immunoglobulin A in Liver Diseases and in Other Diseases with High Serum Immunoglobulin A”, J. Clin. Invest, 71:358-367.; IDS entered), Kalsi et al (IgA in alcoholic cirrhosis. Clin Exp Immunol. 1983 Jun;52(3):499-504.; previously cited), and Anderson et al (US Pat No 12,168,682 B2; previously cited) which all teach methods of detecting IgA and its conformations and subtypes in a biological sample. Additionally, the detection of a biomarker in blood by any means has been specifically identified by the courts as both insignificant extra-solution activity (see MPEP 2106.05(g)) and routine and conventional in the life science arts (see MPEP 2106.05(d)(II)).
Therefore, the claims as a whole do not amount to significantly more than the judicial exception when the claim elements are considered individually or in combination.
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, 3-6, 8, 16, 19, 25, 35, 39-40, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Kalsi et al (IgA in alcoholic cirrhosis. Clin Exp Immunol. 1983 Jun;52(3):499-504.; previously cited) in view of Anderson et al (US Pat No 12,168,682 B2; previously cited).
Regarding claims 1, 8, 16, 19, 35,and 58, Kalsi teaches a method comprising:
Determining the dIgA level and mIgA level in a biological sample from the subject and a ratio thereof and comparing the ratio to a threshold (Abstract: Circulating IgA in patients with alcoholic cirrhosis was quantitated and characterized to determine the proportion of monomer and dimer present. Polymeric IgA formed a significantly greater proportion of the total serum IgA in cirrhosis; Fig. 1 shows that in terms of the % of total IgA in a serum sample, patients with cirrhosis have a lower level of mIgA and a higher level of dIgA than normal healthy control patients; the data reflects that the ratio of dIgA to mIgA in patients with cirrhosis is higher than the threshold ratio of dIgA to mIgA in normal control patients; Pg. 503, Par. 3: the results presented here confirm a striking elevation in serum IgA seen in alcoholic cirrhosis, with a significant increase in the proportion of IgA that is polymeric).
The preamble of claim 1 recites “a method for detecting gut barrier dysfunction and/or cirrhosis in a subject”, however there are no actively recited method steps of detecting or determining gut barrier dysfunction and/or cirrhosis. The normal purpose of a claim preamble is to recite the purpose or intended use of the claimed invention. Such statements merely define the context in which the invention operates and usually will not limit the scope of the claim or distinguish it over the prior art (MPE 2111.02). A preamble is generally not accorded any patentable weight in a case such as this where it merely recites the purpose or a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness, but instead the process steps or structural limitations are able to stand alone (MPEP 2111.02). As it applies to the instant case, the actively recited method steps are able to stand on their own without relying on the preamble for completeness. Accordingly, prior art references such as Kalsi which teach all actively recited steps of the method claim are understood to meet the instant claim, regardless of whether or not they explicitly teach the same intended use.
Kalsi further teaches measurement of total IgA in a sample, and demonstrates that total IgA may be elevated in a sample from a cirrhotic patient as compared to a sample from a normal control patient (Fig. 1). Kalsi differs from the instant claims in that it teaches that dIgA and mIgA are detected by immunoradiometric assay, and does not teach contacting the sample with the specific antibodies or binding agents recited by the instant claims, and does not teach detection comprising the use of a lateral flow device.
Anderson discloses an antibody capture process for determining gut wall integrity in a test subject, wherein the level or ratio of SIgA to dIgA is compared to a corresponding level or ratio from a control subject (Abstract). Anderson teaches that in normal plasma samples, secretory IgA (SIgA) is found only in trace amounts (Col. 19, Ln. 54-62), while about 90% of total IgA is mIgA and the other 10% is dIgA (Col. 2, Ln. 19-28), such that total IgA is made up of SIgA, dIgA, and mIgA. Anderson teaches that SIgA and dIgA may be measured in a sample, wherein an elevated ratio of SIgA to dIgA as compared to a control may indicate leaky gut, and further teaches that the disclosed methods may be used in conjunction with an assay to measure total IgA (end of Col. 3-beginning of Col. 4; Col. 10, Ln. 50-53; Col. 29, Ln. 58-61).
Anderson further teaches that dIgA can be specifically detected in a sample by contacting the sample with a pIgR that binds specifically to dIgA (Col. 3, Ln. 28-38). Anderson teaches that measurements for the disclosed methods may be made by a number of methods known in the art and teaches specifically that lateral flow devices are a convenient format for performing the disclosed measurements and methods (Col. 13, Ln. 4-7: determining the presence or levels of dIgA or pIgR or a complex between dIgA and recombinant pIgR may be by any convenient protocol; Col. 13, Ln. 29-33: immunochromatographic devices are expressly contemplated comprising dIgA-binding reagents such as recombinant pIgR; Col. 22, Ln. 29-33). Anderson teaches that immunochromatographic methods and devices are advantageous over other methods of the prior art such as radioimmunoassay because they require less equipment, skill, and time to use (Col. 13, Ln. 17-28). Anderson teaches that SIgA can be measured in a sample by contacting the sample with an antibody that specifically binds SIgA (Col. 3, Ln. 46-50: contacting the biological sample with an anti-SC binding agent or anti-SC antibody wherein the anti-SC binding agent or anti-SC antibody binds SIgA and forms an SIgA-binding agent/antibody complex).
One of ordinary skill in the art will recognize from these teachings that a lateral flow device can comprise multiple different test lines comprising different capture reagents for different analytes of interest, as taught by Anderson. As such, it would have been obvious to one of ordinary skill in the art before the effective filing date to have modified the invention of Kalsi such that dIgA and mIgA are measured on a lateral flow device. One of ordinary skill in the art would be motivated to make this modification because Anderson teaches that lateral flow devices are convenient point of care assays which require less time, training, and resources than the immunoradiometric assay originally taught by Kalsi. For example, one of ordinary skill would recognize that such a lateral flow device could comprise (in order from upstream end to downstream end of the lateral flow device) immobilized recombinant pIgR at the first test line for detection of dIgA; immobilized anti-SC binding agent/antibody at the second test line for detection of SIgA; and anti-IgA antibody (i.e. an agent which binds mIgA, wherein dIgA and SIgA have been depleted from the sample by the first two test lines such that the third test line can be understood to measure mIgA as the only remaining IgA component in the sample). One of ordinary skill in the art would have a reasonable expectation of success in making this modification because both Kalsi and Anderson are directed to immunoassays for the measurement of different IgA subtypes and conformations.
Regarding claims 3-5, Kalsi teaches the method wherein a difference from the threshold indicates gut barrier dysfunction and/or cirrhosis in the subject; wherein the difference is specifically an increase in the ratio of dIgA to mIgA (Abstract: Circulating IgA in patients with alcoholic cirrhosis was quantitated and characterized to determine the proportion of monomer and dimer present. Polymeric IgA formed a significantly greater proportion of the total serum IgA in cirrhosis; Fig. 1 shows that in terms of the % of total IgA in a serum sample, patients with cirrhosis have a lower level of mIgA and a higher level of dIgA than normal healthy control patients; the data reflects that the ratio of dIgA to mIgA in patients with cirrhosis is higher than the threshold ratio of dIgA to mIgA in normal control patients; Pg. 503, Par. 3: the results presented here confirm a striking elevation in serum IgA seen in alcoholic cirrhosis, with a significant increase in the proportion of IgA that is polymeric).
Regarding claim 6, Kalsi teaches the method of claim 1 as described above, but does not explicitly teach that a dIgA to mIgA ratio greater than or equal to a threshold of 0.65 indicates gut barrier dysfunction in a subject. However, as described in the rejection of claim 1 above, Kalsi demonstrates that an elevated ratio of dIgA to mIgA in a subject as compared to a normal control subject may be indicative of cirrhosis (see Fig. 1), wherein the data shown in Fig. 1 indicates that the mean ratio of dIgA to mIgA in cirrhotic patients is about 0.51, while the mean ratio of dIgA to mIgA in a normal control subject is about 0.23. More specifically, the data shows that cirrhotic patients have a ratio which ranges from 0.24-1.01 while normal control subjects have a ratio which ranges from about 0.06-0.67.
As such, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have determined from the teachings of Kalsi that a dIgA to mIgA ratio above a particular threshold is indicative of alcoholic cirrhosis in a subject. It further would have been obvious to one of ordinary skill in the art to choose a value around 0.65 as the particular threshold for indication of alcoholic cirrhosis, because the data shows that this threshold would exclude almost all healthy control patients tested (8 out of 9) such that false positive diagnoses would be minimized. One of ordinary skill in the art would have a reasonable expectation of making this modification because Kalsi provides teachings and data which support the use of the ratio of dIgA to mIgA as an indicator of cirrhosis.
Regarding claim 25, Kalsi further teaches the method wherein the biological sample is selected from whole blood, plasma serum, or gingiva creviscular fluid (Pg. 500, Par. 4: serum samples).
Regarding claims 39-40, Kalsi further teaches the method wherein the subject is human (Abstract; Pg. 500, Par. 2).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Kalsi et al (IgA in alcoholic cirrhosis. Clin Exp Immunol. 1983 Jun;52(3):499-504.; previously cited) in view of Anderson et al (US Pat No 12,168,682 B2; previously cited) as applied to claim 8 above, and further in view of Hanafiah et al ((2015). Virus-specific dimeric IgA: a new biomarker for acute viral hepatitis infections?. Journal of Viral Hepatitis. 22. 2-2. 10.1111/jvh.02_12424.; previously cited).
Regarding claim 11, the modified invention of Kalsi in view of Anderson discussed above comprises pIgR for binding and detection of dIgA, as taught by Anderson. From the teachings of Anderson, it appears that the pIgR may be a chimeric secretory component, but it is not explicitly described as such (Col. 14, L. 12-34).
Regarding claim 11, Hanafiah teaches that dIgA may be specifically detected by a pIgR which is a chimeric secretory component (Pg. 2, Col. 2, Par. 2: Human pIgR binds with equal affinity to dIgA and pentameric IgM. To bind only dIgA, we cloned a recombinant human/rabbit chimeric secretory component (cSC) or pIgR in a eukaryotic expression vector and transfected 293T mammalian cells. We used the cSc to detect dIgA in serum and plasma samples).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the method of Kalsi in view of Anderson such that the pIgR used to detect dIgA is specifically a chimeric secretory component, as taught by Hanafiah. One of ordinary skill in the art would be motivated to make this modification because Hanafiah teaches that the CSC is a suitable reagent for the specific detection of dIgA without interference from binding of pentameric IgM. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Kalsi, Anderson, and Hanafiah are all directed to the specific detection and measurement of dIgA.
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Kalsi et al (IgA in alcoholic cirrhosis. Clin Exp Immunol. 1983 Jun;52(3):499-504.; previously cited) in view of Anderson et al (US Pat No 12,168,682 B2; previously cited) as applied to claim 35 above, and further in view of Wong et al (Lateral Flow Immunoassay, Humana Press. Pg. 1-5 (2009); previously cited).
Regarding claim 36, Kalsi in view of Anderson teaches the method of claim 35 as described above. Anderson teaches that the lateral flow device may comprise capture antibodies in the test zones and a conjugate portion comprising a detectable label, but does not teach a specific species of conjugate and detectable label used in the lateral flow device (Col. 13, Ln. 29-54). However, in an alternative format, Anderson teaches that labeled anti-IgA can be used in combination with pIgR for the detection of dIgA (Col. 25, Ln. 56-67). Anderson does not teach that the label used is colloidal gold.
Regarding claim 36, Wong teaches that an anti-analyte antibody conjugated to a detectable label such as a gold colloid is a commonly used detection conjugate in a lateral flow device (Pg. 3: conjugate pad comprising a particulate conjugate which is typically colloidal gold. The particle has been conjugated to one of the specific biological component of the assay such as an antigen and antibody).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the lateral flow device of Kalsi in view of Anderson to specifically comprise a detection reagent comprising anti-human IgA colloidal gold. One would be motivated to make this modification because Anderson teaches that anti-human IgA conjugated to a detectable label can be used for the detection of specific types of IgA in an immunoassay comprising other anti-IgA capture antibodies, and Wong teaches that gold colloid is a commonly used detectable label in a lateral flow device. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Kalsi in view of Anderson teaches a lateral flow device comprising a labeled conjugate which may comprise anti-human IgA antibody, and Wong teaches that colloidal gold may be used as a detectable label on an antibody conjugate in an lateral flow immunoassay. An anti-human IgA conjugated to colloidal gold would be a suitable conjugate for the lateral flow immunoassay because it is a single species of conjugate which can be used to label target analyte for all three test lines on the lateral flow device of Kalsi in view of Anderson and Wong.
Claim 46 is rejected under 35 U.S.C. 103 as being unpatentable over Kalsi et al (IgA in alcoholic cirrhosis. Clin Exp Immunol. 1983 Jun;52(3):499-504.; previously cited) in view of Anderson et al (US Pat No 12,168,682 B2; previously cited) as applied to claim 1 above, and further in view of Starr et al (Cirrhosis: diagnosis, management, and prevention. Am Fam Physician. 2011 Dec 15;84(12):1353-9.; previously cited).
Regarding claim 46, Kalsi in view of Anderson teaches the method claim 1 as described above, and teaches that elevated ratios of dIgA to mIgA in a subject as compared to normal controls is indicative of cirrhosis (see Fig. 1). Kalsi does not explicitly teach a step of identifying a patient as having cirrhosis and administering an appropriate treatment to the identified patient.
Starr as a whole is directed to the diagnosis and treatment of cirrhosis (Abstract). Throughout the reference Starr discusses the importance of medical intervention and treatment of alcoholic cirrhosis and discloses a number of different options for the treatment of cirrhosis after diagnosis.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kalsi to explicitly include a step of identifying a patient as having cirrhosis and administering an appropriate treatment to the identified patient as taught by Starr. One of ordinary skill in the art would be motivated to make this modification because Starr teaches that cirrhosis is a serious condition which requires ongoing treatment and management for the benefit of the patient. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Kalsi teaches a method of differentiating cirrhotic patients from healthy patients, while Starr indicates appropriate courses and methods of treatment for patients who are diagnosed with cirrhosis.
Subject Matter Free of Prior Art
Claims 13 and 59 are rejected as described above, but appear to be free of the prior art.
The closest prior art is Kalsi, Delacroix, and/or Anderson as described in the rejection above, and as described at length in the rejections of the Non-Final Rejection dated 29 August 2025, however, neither reference teaches specific detection of the level of mIgA1 in the sample.
Regarding claim 13, the prior art references comprise teachings for the first embodiment of claim 1 (determining dIgA and mIgA in a sample…) but do not specifically teach the second embodiment of claim 1 (determining the dIgA1 or dIgA2 level and mIgA1 and mIgA2 level…). Claim 13 is generally understood to refer to/further limit the second embodiment of claim 1, due to the recitation of “the mIgA1 level” (wherein a “mIgA1 level” is specifically introduced in the second embodiment of claim 1).
Even if claim 13 is interpreted to possibly depend from/further limit the first embodiment of claim 1, the prior art does not contain sufficient teachings which would make it obvious to one of ordinary skill in the art to modify the first embodiment of claim 1 such that the method would include specific measurement of mIgA1 in addition to measurement and determination of a ratio for dIgA and mIgA. Kalsi and Delacroix do not teach measurement of mIgA1 specifically, and while other prior art references contain teachings about the measurement of mIgA specifically (see Deviere et al (IgA triggers tumor necrosis factor alpha secretion by monocytes: a study in normal subjects and patients with alcoholic cirrhosis. Hepatology. 1991 Apr;13(4):670-5. ); previously cited) or teach reagents which are capable of measurement of mIgA1 specifically (see Lorin et al (Efficient generation of human IgA monoclonal antibodies. J Immunol Methods. 2015 Jul;422:102-10.; previously cited)), these teachings do not provide motivation which would make it obvious to one of ordinary skill in the art to further modify the method of claim 1 to meet the specific limitations of claim 13.
Similarly, Kalsi, Delacroix, and Anderson are the closest prior art references for claim 59. Kalsi in view of Anderson teaches amended claim 1, as described above. Kalsi contains no teaching or discussion of measuring IgA1 components and IgA2 components specifically.
Anderson contains some discussion of the utility of measuring certain IgA2 components, however, in those instances, Anderson primarily discusses measuring a ratio of SIgA2 and dIgA2 (see, e.g. Col. 10, 17, 20). This teaches away from the instant claim which specifically requires that IgA2 is measured after a sample is contacted with the test strip comprising the dIgA binding agent. As such, sample would necessarily be depleted of dIgA2 prior to contacting the IgA2 binding agent, such that the teachings of Anderson regarding the utility of measuring a ratio of SIgA2 and dIgA2 do not provide motivation for producing the method as claimed.
Delacroix also discusses measurement of IgA2, but teaches measurement of IgA2 specifically within the context of measuring IgA2 as a proportion of total IgA. As with Anderson, this teaches away from the embodiment of instant claim 59 which indicates depletion of dIgA from the sample prior to contact with the IgA2 binding agent, such that the method of claim 59 is not suitable for the detection of IgA2 as a proportion of total IgA, as discussed in Delacroix. As such, Delacroix does not provide motivation or teaching to meet the instant claim.
Response to Arguments
Applicant’s arguments filed 26 December 2025 have been fully considered.
Applicant’s arguments regarding sequence disclosure, specification objections, and claim objections are persuasive in view of the amendments to the claims and the specification, and these objections are withdrawn.
Applicant’s arguments regarding the previous 112(b) rejections are persuasive in view of the amendments to the claims for all prior 112(b) rejections except that of claim 16. The 112(b) rejection of claim 16 is maintained, and all other previous 112(b) rejections are withdrawn.
Regarding the 112(a) rejections, Applicant argues that the arbitrary units used to calculate ratios of IgA as shown in Fig. 6 are representative of actual dIgA and mIgA levels calculated in those samples, and that thus one of ordinary skill in the art would reasonably predict that the results could be extrapolated or expanded to other methods and devices than those provided in the specific examples. This argument is not persuasive because the specification does not provide showing of how these arbitrary units are related to a unit which would be conserved and recognized by one of ordinary skill in the art or in a method that employs variations in detection. That is, the method relies upon comparing data to a specific threshold (e.g. such as those provided in claim 6). While one of ordinary skill in the art would recognize that the provided arbitrary units are representative of amounts/concentrations of the markers measured, the specification does not provide any data or showing of specific concentrations or amounts calculated from the arbitrary units and does not support the assertion that any arbitrary units yielded from any method encompassed by the instant claims would yield the same critical/numerical threshold ratio of IgA components, thus there is insufficient evidence that the inventors had possession of the full scope of the invention as claimed at the time of filing.
Regarding the determination of ratios of dIgA1/2 and/or mIgA1/2, Applicant asserts that support is provided at Fig. 12 and at Pg. 33, Ln. 14-20 of the PCT specification as filed which indicates that levels of both dIgA1 and dIgA2 are significantly elevated in cirrhosis patients relative to healthy controls, suggesting that dIgA1 and/or dIgA2 could be used as alternative to total dIgA in determination of gut leakage/cirrhosis using the claimed method. This evidence is noted and acknowledged, but the argument is not persuasive because the evidence is insufficient to support possession of the entire scope of the claim. That is, there is no discussion or showing of mIgA1 or mIgA2 measurements in particular, and no disclosure of a threshold ratio as claimed for the particular elements measured in these embodiments. That is, a suggestion that dIgA1 and/or dIgA2 may be used as an alternative to total dIgA, does not fully support the assertion that the inventors had possession at the time of filing of a method where a particular threshold ratio of, for example dIgA1 to mIgA2 is used for determination and diagnosis of cirrhosis or gut barrier dysfunction.
The previous 112(a) rejection is withdrawn in view of the amendments to the claims, but new grounds of 112(a) rejection which address the amended claims are presented above.
Regarding the 101 rejections, Applicant argues that the additional elements of the claims are sufficient to provide significantly more than the recited judicial exceptions (i.e. that the specific method steps of contacting a sample to different IgA binding agents on a test strip in a particular order constitutes significantly more than the judicial exception and is not routine and conventional in the art). This argument is not persuasive in light of the prior art cited in the rejection above which teaches detection and measurement of IgA subtypes and conformations in a biological sample from a subject, and specifically in light of the teachings of Anderson which specifically disclose measurement of IgA subtypes and conformations on a test strip by the use of binding agents which specifically bind to dIgA and mIgA as recited in the claims.
Regarding the previous 102 and 103 rejections, Applicant argues that the previous rejections do not sufficiently teach the amendments to the claims. This argument is persuasive in view of the amendments to the claims, and the previous 102 and 103 rejections are withdrawn, and are replaced with the new grounds of 103 rejection presented above.
Applicant’s arguments provide assertions that the instantly disclosed method carries advantages which are not provided by the methods disclosed by Kalsi or Delacroix. These arguments are not persuasive because some of the claimed advantages are not elements recited in the claims and because the rejection provided above does not rely solely on either Kalsi or Delacroix.
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.
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/ELLIS FOLLETT LUSI/Examiner, Art Unit 1677
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677