DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
This is a U.S. application that claims priority to U.S. Provisional Application No. 63/552,960 filed
on 02/13/2024 and to U.S. Provisional Application No. 63/458,526 filed on 04/11/2023.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/17/2024, 07/16/2024 and 08/06/2024 have been received. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner and all references are considered except where they were lined through.
Claim Objections
Claim 1 is objected to because of the following informalities: the claim recites the abbreviation “proUGN” without providing a definition for the term. To move prosecution, proUGN is read as prouroguanylin. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-32 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 measuring full length prouroguanylin (proUGN) or SEQ ID No. 1, does not reasonably provide enablement for measuring any fragment or variant of proUGN. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Regarding claims 1 and 24, the claims respectively provide a method of treating a subject for stage 3 or stage 4 CKD or a method of treating a subject for pre-CKD based on respectively comparing proUGN to a reference value of 2.241 ng/ml or to a reference range of 2.05 ng/ml to and including 2.24 ng/ml. And claims 18 and 28 respectively further recite a method for diagnosing a subject for stage 3 or stage 4 chronic kidney disease (CKD) or a method for diagnosing a subject for pre-CKD by measuring the concentration level of proUGN in a biological sample to respectively compare to a reference value of 2.241 ng/ml or to a reference range of 2.05 ng/ml to and including 2.24 ng/ml. The specification does not provide enough support for an artisan to perform the assay without undue additional experimentation as described in re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1998) as appropriate. See also MPEP § 2164.01(a) and § 2164.04.
The breadth of the claims:
Claims 1 and 24 are recited at a high level of generality by respectively treating a subject for stage 3/4 CKD or for pre-CKD based on respectively comparing proUGN to a reference value of 2.241 ng/ml or to a reference range of 2.05 ng/ml to and including 2.24 ng/ml. Claims 1 and 24 do not specify if the full length (SEQ ID No. 1), a fragment or a variant of proUGN is measured for the comparison. Similarly, claims 18, and 28 are also recited at a high level of generality in which the concentration of full length (SEQ ID No. 1), any fragment or any variant of proUGN is measured with any assay to respectively compare to a reference value of 2.241 ng/ml or to a reference range of 2.05 ng/ml to and including 2.24 ng/ml to respectively diagnose a subject for stage 3/4 CKD or for pre-CKD. Thus, claims 1, 18, 24 and 28 are recited at a high level of generality.
The nature of the invention:
The invention is for a method of treating a subject for stage 3/4 CKD or a method of treating a subject for pre-CKD based on respectively comparing proUGN to a reference value of 2.241 ng/ml or to a reference range of 2.05 ng/ml to and including 2.24 ng/ml, and the comparison does not specify if the full length (SEQ ID No. 1), a fragment or a variant of proUGN is measured for the comparison. The invention is also about a method for diagnosing a subject for stage 3 or stage 4 chronic kidney disease (CKD) or a method for diagnosing a subject for pre-CKD by measuring the concentration level of full length (SEQ ID No. 1), a fragment or a variant of proUGN to compare to a reference value of 2.241 ng/ml to a reference range of 2.05 ng/ml to and including 2.24 ng/ml.
The state of the prior art:
Although there has been an earlier report of measuring proUGN with antibodies as noted by Coughlin et al. (US 2021/0263047 A1, priority to 01/31/2020), Coughlin does not teach using antibodies to any fragment or variant of proUGN. Also, while there are commercially available antibodies to proUGN as noted by Folgueira et al. (Scientific Reports volume 8, Article number: 14541 (2018), page 3 of 8, fifth paragraph, “The quantitative measurement of pro-UGN in plasma samples was performed using a commercial enzyme-linked immunosorbent assay (ELISA) kit for Human guanylate cyclase activator 2B, uroguanylin (GUCA2B, CSB-EL010048HU; CUSABIO BIOTECH CO., LTD, Wuhan, China)”), Folgueira does not teach using antibodies to any fragment or variant of proUGN. Furthermore, in re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case here where there is a relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims of the instant application.
The level of one of ordinary skill:
Based on the absence of prior art that describes using antibodies to any fragment or variant of
proUGN, the level of a person having ordinary skill in the art is not high enough to use any antibodies to any fragment or variant of proUGN.
The level of predictability in the art:
There is a high level of unpredictability in using antibodies to any fragment or variant of proUGN because it is not known which fragment or variant of an antigen is capable of eliciting an immune response when making the antibodies as noted by Tiller et al. (Annu. Rev. Biomed. Eng. 2015. 17:191–216, page 193, first paragraph, “At the discovery stage, immunization affords limited control over antibody affinity and specificity due to the difficulty in controlling antigen presentation to the immune system”). And also, it is not known which fragment or variant is successfully detected in the circulation of a subject because the prior art does not teach using antibodies to any fragment of variant of proUGN as noted by Coughlin and Folgueira. While Coughlin and Folgueira teach detecting proUGN with antibodies, Coughlin and Folgueira do not teach detecting any fragment or variant of proUGN. Thus, it cannot be predicted which fragment or variant of proUGN will be detected in the circulation before testing.
The amount of direction provided by the inventor:
As discussed above, the art does not teach detecting any fragment or variant of proUGN.
The specification provides two examples without discussing using antibodies to any fragment or variant of proUGN. Specifically, Example 1 teaches a phase 2 validation study to evaluate the proUGN for kidney function, detection, or diagnosis, and/or management of kidney disease using the immunological assay of enzyme-linked immunosorbent assay (ELISA) disclosed in U.S. Patent Publication No. 2021/0263047 which does not use antibodies to any fragment or variant of proUGN (Example 1, pages 17-28). Example 1 further teaches that circulating proUGN was quantitatively measured via a monoclonal antibody (mAb) sandwich ELISA (Page 20, second paragraph). Example 2 teaches measuring proUGN in patients of high-risk of CKD (i.e., patients with comorbidities commonly associated with CKD) (Pages 28-30).
Examples 1-2 do not provide a plan or a method for how to design and test the functionality and structure of any antibody to any fragment or variant of proUGN. The specification only briefly discusses the full length proUGN and two N-terminal fragments of the proUGN (page 7-9), but does not provide examples for using the N-terminal fragments nor for any fragment or variant of proUGN. Thus, the specification of the instant application fails to address a method that uses any fragment or variant of proUGN and is not commensurate in scope with the broad claims of the instant application.
The existence of working examples:
The examples of the specification only teach measuring proUGN as noted above without describing any of the fragments or variants of proUGN (Example 1, pages 17-28; Example 2, pages 28-30). Example 1 of the specification is about how to validate the use pf proUGN in evaluating kidney function and disease (Example 1, page 28). Example 2 is about further measuring proUGN in patients with comorbidities commonly associated with CKD (Example 2, pages 28-30).
The examples are directed to only measuring proUGN without teaching how to measure fragments or variants of proUGN. Furthermore, there is no indication from the examples that the broadly claimed methods would work in any type of assay with any diagnostic platform and with any fragment or variant of proUGN.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
With the lack of teaching in prior art in regards to measuring fragments or variants of proUGN, the PHOSITA is expected to face an unreasonable amount of experimentation. Furthermore, the emergence of proUGN use for diagnosing CKD or pre-CKD at the time the application was filed adds another challenge to a PHOSITA or to a clinician.
Thus, the specification of the instant application does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with claims 1-32 of the instant application. Consequently, claims 1-32 are rejected under 35 U.S.C. 112(a) because the specification while being enabling for measuring full length prouroguanylin (proUGN) or SEQ ID No. 1, does not reasonably provide enablement for measuring any fragment or variant of proUGN.
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 1-32 are rejected under 35 U.S.C. 101 because the claimed invention is for a process or a method that is directed to at least one judicial exception without significantly more. The claims recite a mere collection of information in the form of data that is compared to a reference value or range of values of prouroguanylin (proUGN) from which the applicant or doctor will be able to diagnose a subject for chronic kidney disease (CKD) or for pre-chronic kidney disease (pre-CKD) and to treat accordingly. Such an inference is not sufficient to transform the abstract idea of a mental process of comparing the proUGN concentration to a reference value or to a range of values of proUGN and a law of nature of correlating the proUGN concentration with subject’s diagnosis and treatment for CKD or for pre-CKD into a patentable application.
The claims are ineligible because they recite at least one judicial exception, i.e., an abstract idea of a mental process (comparing the concentration of proUGN to a reference value or to a range of values of proUGN), and a law of nature (correlating the proUGN concentration with subject’s diagnosis and treatment for CKD or for pre-CKD). Moreover, the claims as a whole do not integrate the judicial exceptions into a practical application nor do they provide an inventive concept.
Although there is a proposed treatment step in claims 1 and 24 it is a general step that does not add significantly more to the judicial exceptions of the instant application. Specifically, claim 1 recites “administering a CKD-therapeutic agent to a subject in need” which is a general treatment that encompass a wide range of therapeutic agents such as sodium-glucose cotransporter-2 (SGLT2) inhibitor; a potassium-sparing diuretic / selective mineralocorticoid-receptor antifibrotic/pyridine. Claim 24 has an even broader treatment as it recites ” providing lifestyle and/or dietary modification instructions to the subject” which is also a general treatment that does not specify what type of treatment is to be administered. Thus, the steps in claims 1 and 24 do not add significantly more to the judicial exceptions of the instant application, and therefore, the judicial exceptions are not integrated into a practical application.
Step 1: Is the claim to a process, machine, manufacture or composition of matter?)
This part of the eligibility analysis evaluates whether the claim falls within any statutory category per MPEP 2106.03.
Example 43 of 2019 Revised Patent Subject Matter Eligibility Guidance (PEG) is particularly enlightening because the fact pattern of claim 1 of example 43 is most similar to the instant application claims (Subject matter eligibility | USPTO)
Regarding claim 1 of example 43 of the PEG and per Step 1, the claim is directed to a process, which is one of the statutory categories of invention as the claim recites “A treatment method comprising: (a) calculating a ratio of C11 to C13 levels measured in a blood sample from a patient diagnosed with Nephritic Autoimmune Syndrome Type 3 (NAS-3) to identify the patient as having a non-responder phenotype; (b) administering a treatment to the patient having a non-responder phenotype.” (Step 1: YES).
Similarly, claim 1 of the instant application is also directed to a statutory class of a method of treating stage 3 or stage 4 chronic kidney disease (CKD) by administering a CKD-therapeutic agent to a subject in need, wherein the subject has a proUGN concentration level of 2.241 ng/ml or higher in
a biological sample of the subject (Step 1: YES).
And claim 8 of the instant application is directed to a statutory class of a method for diagnosing stage 3 or stage 4 CKD in a subject by measuring a concentration level of proUGN in a biological sample of the subject, wherein a concentration level of proUGN of 2.241 ng/ml or higher indicates that the subject is positive for stage 3 or stage 4 CKD (Step 1: YES).
Also, claim 24 of the instant application is directed to a statutory class of a method of treating pre-CKD in a subject in need by providing lifestyle and/or dietary modification instructions to the subject to decrease progression to CKD, wherein the subject has a proUGN concentration level of 2.05 ng/ml to and including 2.24 ng/ml in a biological sample of the subject (Step 1: YES).
And claim 28 of the instant application is also directed to a statutory class of a method for diagnosing pre-CKD in a subject by measuring a concentration level of proUGN in a biological sample of the subject, wherein a concentration level of 2.05 ng/ml to and including 2.24 ng/ml indicates that the subject is positive for pre-CKD (Step 1: YES).
(Step 2A, Prong 1: Does the claim recite an abstract idea, law of nature or natural phenomenon?)
Claim 1 of example 43 of PEG recites judicial exceptions that are similar to claims 21 and 25 of the instant application. Specifically, and per Step 2A, prong 1, claim 1 of example 43 of PEG recites the judicial exception of “calculating a ratio of C11 to C13 levels measured in a blood sample from a patient diagnosed with Nephritic Autoimmune Syndrome Type 3 (NAS-3) to identify the patient as having a non-responder phenotype,” and according to broadest reasonable interpretation (BRI), an arithmetic calculation of a division is required to obtain the ratio of C11 to C13 that can be used to identify whether the patient has the non-respondent phenotype (i.e., the patient has a calculated ratio of 3:1 or greater and thus is not responding, or will not respond, to glucocorticoids). This limitation therefore recites a mathematical calculation. And the grouping of “mathematical concepts” in PEG includes “mathematical calculations” as an exemplar of an abstract idea. PEG Section I, 84 Fed. Reg. at 52. Thus, limitation (a) of claim 1 of PEG falls into the “mathematical concept” grouping of abstract ideas.
Similarly, claims 1, 18, 24 and 28 of the instant application also recite a judicial exception of an abstract idea of a mental process of comparing the concentration of proUGN to a reference value or to a range of values of proUGN. Specifically claim 1 recites “wherein the subject has a proUGN concentration level of 2.241 ng/ml or higher in a biological sample of the subject” and claim 18 recites “measuring a concentration level of proUGN in a biological sample of the subject, characterized in that a concentration level of proUGN of 2.241 ng/ml or higher indicates”. Moreover, claim 24 recites “wherein the subject has a proUGN concentration level of 2.05 ng/ml to and including 2.24 ng/ml in a biological sample of the subject” and claim 28 recites “measuring a concentration level of proUGN in a biological sample of the subject, characterized in that a concentration level of 2.05 ng/ml to and including 2.24 ng/ml indicates”.
Also, limitation (a) of claim 1 of PEG describes a naturally occurring relationship between the ratio of C11 to C13 and the non-responder phenotype, and thus may also be considered to recite a law of nature.
Furthermore, claims 1, 18, 24 and 28 also describe a naturally occurring relationship between proUGN concentration and subject’s diagnosis and treatment for CKD or for pre-CKD, and thus are considered to recite a law of nature. Specifically, claim 1 recites “A method of treating stage 3 or stage 4 chronic kidney disease (CKD) … wherein the subject has a proUGN concentration level of 2.241 ng/ml or higher in a biological sample of the subject” and claim 18 recites “characterized in that a concentration level of proUGN of 2.241 ng/ml or higher indicates that the subject is positive for stage 3 or stage 4 CKD”. Claim 24 further recites “A method of treating pre-CKD in a subject in need … wherein the subject has a proUGN concentration level of 2.05 ng/ml to and including 2.24 ng/ml in a biological sample of the subject” and claim 28 recites “characterized in that a concentration level of 2.05 ng/ml to and including 2.24 ng/ml indicates that the subject is positive for pre-CKD”.
Accordingly, limitation (a) of claim 1 of PEG recites three judicial exceptions (an abstract idea that falls within the mathematical concept, a mental process groupings in PEG, and a law of nature); whereas claims 1, 18, 24 and 28 of the instant application also recite two judicial exceptions of an abstract idea of a mental process and a law of nature, and the analysis must therefore proceed to Step 2A Prong Two.
(Step 2A, Prong 2: Does the claim recite additional elements that integrate the judicial exception into a practical application?)
Per Step 2A, prong 2, claim 1 of example 43 of PEG and claims 21 and 25 of the instant application as a whole do not integrate the recited judicial exception into a practical application of the exception. Specifically, this evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. Besides the abstract idea, claim 1 of example 43 of PEG recites the additional element of “(b) administering a treatment to the patient having a non-responder phenotype”. Although this limitation indicates that a treatment is to be administered, it does not provide any information as to how the patient is to be treated, or what the treatment is, but instead covers any possible treatment that a doctor decides to administer to the patient. In fact, this limitation is recited at such a high level of generality that it does not even require a doctor to take the calculation step’s outcome (the patient’s phenotype) into account when deciding which treatment to administer, making the limitation’s inclusion in this claim at best nominal. Thus, limitation (b) of example 43 of PEG fails to meaningfully limit the claim because it does not require any particular application of the recited calculation, and is at best the equivalent of merely adding the words “apply it” to the judicial exception. Accordingly, limitation (b) of example 43 of PEG does not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception.
Similar to claim 1 of example 43 of PEG, claims 1, 18, 24 and 28 of the instant application do not have additional elements that would integrate the judicial exceptions cited above into a practical application. The claims have steps of determining the proUGN concentration to compare to a reference value or range of values for proUGN to assess the subject for CKD or pre-CKD to treat accordingly, and these steps do not integrate the judicial exceptions into a practical application because they are data gathering steps to use in the measurement and comparison, which do not add a meaningful limitation to the method as they are insignificant extra-solution activity. These steps do not integrate the judicial exceptions into a practical application because they do not amount to more than the judicial exceptions themselves, analogous to Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 80, 84, 101 USPQ2d 1961, 1968-69, 1970 (2012). Furthermore, the claim does not act on or use the judicial exceptions in any further steps as required by MPEP 2106.04(d). In the instant case, the doctor is only not required to perform any further action based on the assessment of a subject for CKD or pre-CKD as in claims 18 and 28, whereas claims 1 and 24 only recommend providing a general treatment to the subject. Therefore, claims 1, 18, 24 and 28 of the instant application do not integrate the judicial exceptions into a practical application.
(Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?)
Per Step 2B, claim 1 of example 43 of PEG and claims 21 and 25 of the instant application do not recite additional elements that amount to significantly more than the judicial exception. Specifically, this part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. MPEP 2106.05. As explained with respect to Step 2A Prong Two, claim 1 of example 43 of PEG recites a single additional element in limitation (b), which does not require any particular application of the recited calculation and is at best the equivalent of merely adding the words “apply it” to the judicial exception. Mere instructions to apply an exception cannot provide an inventive concept (Step 2B: NO). The claim is not eligible.
Similarly, claims 1, 18, 24 and 28 of the instant application simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, such as determining the amount of proUGN for example with a commercially available assay such as with ELISA (Specification, page 13, [0055]; page 17, [0069]). Furthermore, the claims themselves are recited at a high level of generality in which any assay can be used as the measurement method for claims 1, 18, 24 and 28.
Thus, claims 1, 18, 24 and 28 are not eligible and are rejected under 35 USC 101.
Regarding claims 2-7, the claims recite the subject’s health condition which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 8-12, 21 and 30, the claims provide more general agents for treating CKD which do not integrate the judicial exception into a practical application, nor do they amount to significantly more.
Regarding claims 13-14 and 19 and 25, the claims define the type of sample which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 15, the claim describes proUGN which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claims 16-17, 22-23, 26-27 and 31-32, the claims further measure additional biomarkers which do not integrate the judicial exception into a practical application, nor do they amount to significantly more.
Regarding claim 20 and 29, the claims suggest the type of assay which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Conclusion
No claims are allowed.
Claims 1-32 are free of prior art because there is prior art before the effective filing date of the instant application of 04/11/2023 that teaches or suggests a method for diagnosing and treating a subject for stage 3 or stage 4 chronic kidney disease (CKD) by measuring the concentration level of proUGN and comparing it to a reference value of 2.241 ng/ml. Also, there is not prior art before the effective filing date of the instant application of 04/11/2023 that teaches or suggests a method for diagnosing and treating pre-CKD in a subject by measuring the concentration level of proUGN and comparing it to a reference range of 2.05 ng/ml to and including 2.24 ng/ml
The closest prior art is discussed below:
While Coughlin et al. (US 2021/0263047 A1, priority to 01/31/2020) teaches a method of diagnosing and treating a subject for chronic kidney disease by measuring the concentration level of proUGN (Abstract), Coughlin does not teach nor suggest comparing the measured proUGN to a reference value of 2.241 ng/ml. Also, Coughlin does not teach nor suggest a method for diagnosing and treating pre-CKD in a subject by measuring the concentration level of proUGN and comparing it to a reference range of 2.05 ng/ml to and including 2.24 ng/ml.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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