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.
Status of Claims
Claims 3-7 are pending and under examination.
Claim Objections
Claim 5 is objected to because of the following informalities: Claim 5 recites Eph needs to be accompanied by an unabbreviated form. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 5 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 5 recites “the substance that specifically binds to the Ephrin-B is a specific antibody to the Ephrin-B or an Eph” is unclear to the metes and bounds of whether the antibody is specifically to both Ephrin-B and Eph; or the substance that specifically binds to the Ephrin-B is an Eph? If the claim is rewritten to recite “an Eph or a specific antibody to the Ephrin-B”, then it would overcome the rejection. For prosecution, the claim is interpreted that the substance is an Eph, as Eph binds to Ephrin-B.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 5 recites “a specific antibody to the Ephrin-B or an Eph” is broaden the scope of the claimed invention as the substance now can be specific to Eph. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 3-6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and nature/natural phenomena without significantly more.
Step 1: The instantly claimed invention is directed to a method examining nephrotic syndrome comprising measuring the expression level of an Ephrin-B in the urine of a subject and also directed to a diagnostic reagent only comprising a substance that specifically binds to an Ephrin-B. Therefore, the instantly claimed invention falls into one of the four statutory categories. (Step 1: YES).
ELIGIBILITY STEP 2A; WHETHER A CALIM IS DIRECTED TO A JUDICIAL EXCEPTION. First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
STEP 2A: Prong One
Claim 3 recites the following steps which fall under abstract ideas and nature/natural phenomena: The claim is drawn to examining nephrotic syndrome and the natural correlation between nephrotic syndrome with Ephrin-B biomarker and/or the presence of Ephrin-B in urine samples.
In particular, these limitations are directed to the judicial exceptions because the claim language clearly conveys mental processes/concepts performed in the human mind (such as thinking). Such step would read on purely mental activity such as a practitioner looking at a subject’s chart and thinking about the concentrations of Ephrin-B. Additionally, the naturally occurring relationship between the levels of Ephrin-B and nephrotic syndrome/or urine samples constitute law of nature/natural phenomena, as the levels of Ephrin-B correlate with nephrotic syndrome/or urine samples.
Also, claim 4 recites the following substance which fall under a natural product: The claim is drawn to a diagnostic reagent that is a substance (e.g., Nephrin or Eph) which is naturally produced in the body to bind Ephrin-B. The phrase “diagnostic reagent” does not provide any structural limitation of the claimed product.
With respect to claim 5, the claim recites wherein the substance that specifically binds to the Ephrin-B is an Eph, which is a natural product. Because the claim recites a substance that has to bind to Ephrin-B and Eph also binds to Ephrin-B, the antibody is only referring to the Ephrin-B.
STEP 2A: Prong Two
Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. Besides the natural phenomenon and mental processes limitations, claim 3 recites measuring the expression level of an Ephrin-B. Although these limitations indicate the active step of measuring, it does not provide any information on the purpose of measuring the expression level, but instead covers any possible reasons of measuring the expression level. Therefore, these limitations constitute to insignificant extra-solution activity. When so evaluated, this additional element represents mere for data gathering (obtaining information) that is necessary for use of the recited judicial exception and is recited at a high level of generality.
With respect to claim 6, the claim is drawn to the natural substance with a buffer. The specification only discloses that the antibody is in a buffer solution. The specification does not provide any disclosure on the difference in structural properties between the substance in a buffer and lack thereof. Accordingly, the claimed combination does not mark different characteristics of the substance when in a buffer solution. Additionally, there is not definition of the claimed buffer. Because the substance is in a subject that contains water and water is known as a poor buffer, the recitation of a buffer does not integrate the judicial exception into a practical application.
Accordingly, this judicial exception is not integrated into a practical application as indicated above (Step 2A Prong 2: NO).
STEP 2B:
In STEP 2B it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP 2106.05. The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception.
Fukusumi et al. (“Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway”, J. Am. Soc. Nephrol, vol. 29, pgs. 1462-1474, published 2018) teach in Fig. 1 measuring Ephrin-B1 and Ephrin-B2 (A) and further measuring said proteins in a urinary protein-to-creatinine ratio (C) (also see caption). Fukusumi teaches the expressions of ephrin-B1 and nephrin clearly decreased when proteinuria peaked and that the remaining ephrin-B1 and nephrin of which major parts were phosphorylated, were dissociated (see pg. 1473, left col., para. 2).
Fehnel et al. (“Dysregulation of the EphrinB2−EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients”, Experimental & Molecular Medicine (2020), vol 52, pgs. 658–671, published 04/14/2020) teach investigating (1) EphrinB2 and EphB4 receptor expression (see abstract). Fehnel further teaches the expression of said Ephrin was assessed in urine (by ELSIA) from pediatric patients with AVM and EphrinB2 expression was increased in AVM tissue, which correlated with increased urinary EphrinB2 levels in AVM patients (see abstract).
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to the judicial exceptions without significantly more. For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 3-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fehnel et al. (“Dysregulation of the EphrinB2−EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients”, Experimental & Molecular Medicine (2020), vol 52, pgs. 658–671, published 04/14/2020).
Fehnel teaches investigating (1) EphrinB2 and EphB4 receptor expression in cerebral AVM and the impact of an altered EphrinB2:EphB4 ratio on brain endothelia cell function (see abstract). Fehnel further teaches the expression of said Ephrin was assessed in urine (by ELSIA) from pediatric patients with AVM and EphrinB2 expression was increased in AVM tissue, which correlated with increased urinary EphrinB2 levels in AVM patients (see abstract). Fehnel also teaches post-treatment urinary EphrinB2 levels normalized in an index patient (see abstract).
With respect to the preamble “for examining nephrotic syndrome”, MPEP 2111.02(II.) states: The claim preamble must be read in the context of the entire claim. The determination of whether preamble recitations are structural limitations or mere statements of purpose or use "can be resolved only on review of the entirety of the [record] to gain an understanding of what the inventors actually invented and intended to encompass by the claim" as drafted without importing "‘extraneous’ limitations from the specification." Corning Glass Works, 868 F.2d at 1257, 9 USPQ2d at 1966. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020) (The court found that the preamble in one patent’s claim is limiting but is not in a related patent); Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999) (Emphasis added).
In this particular case, without a definition, the limitation “for examining nephrotic syndrome” does not provide any additional structure to the body of the claimed invention. If any general subject that is being measured for the expression level of Ephrin-B in urine would read on the claimed method. The preamble does not provide structural limitations to the construction of the claimed method nor does the body define how the measurement is being used. As stated above, the body of a claim fully and intrinsically sets forth all of the limitations of the claimed method, and the preamble merely states the purpose of the invention, which does not have any structural limitation to claim construction.
With respect to claims 4-6, Fehnel teaches the expression of said Ephrin was assessed in urine (by ELSIA) (see abstract). Fednel further teaches the commercially available ELISA assays were procured to test EphrinB2 (and pg. 660, right col., last para.). Performing ELISA would contain an antibody, labeling reagent, a reaction-stopping solution, and/or a buffer.
Claims 3-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fukusumi et al. (“Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway”, J. Am. Soc. Nephrol, vol. 29, pgs. 1462-1474, published 2018, IDS dated 08/17/2023, cite no. 3).
With respect to claim 3, Fukusumi teaches through interactions with nephrin, ephrin-B1 maintains the structure and barrier function of the slit diaphragm (see abstract, conclusion). Fukusumi teaches the expression of ephrin-B1 as well as nephrin was clearly reduced in glomeruli of a patient with relapsing nephrotic syndrome (see pg. 1470, right col., bottom of para. 2). Fukusumi teaches in Fig. 1 measuring Ephrin-B1 and Ephrin-B2 (A) and further measuring said proteins in a urinary protein-to-creatinine ratio (C) (also see caption). Fukusumi teaches the expressions of ephrin-B1 and nephrin clearly decreased when proteinuria peaked and that the remaining ephrin-B1 and nephrin of which major parts were phosphorylated, were dissociated (see pg. 1473, left col., para. 2). Because the claim recites “expression level of an Ephrin-B” and Ephrin-B is localized (expressed) at the slit the diaphragm of glomerular podocytes (see abstract), the expression level could be zero as indicated in Fig. 1C (see control and CKO). In particular, Fukusum teaches the effect of podocyte-specific ephrin-B1 conditional knockout (CKO) (see pg. 1463, left col., para. 2, Figs. 1A-C). Therefore, the behavior of CKO in Fig. 1C would indicate that expression level of Ephrin-B1 based on the protein/creatinine ratio in urine sample.
With respect to claim 4, Fukusumi teaches nephrin binds to Ephrin-B1 (see Fig. 8C), which reads on a substance that specifically binds to an Ephrin-B. Fukusumi further teaches anti-nephrin, anti-phospho Ephrin-B and anti-Ephrin-B1 would read on the structure of the antibody that binds to Ephrin-B or Eph (see Fig. 7A).
With respect to claim 5, Fukusumi teaches anti-phospho Ephrin-B and anti-Ephrin-B1 would read on the structure of the antibody that binds to Ephrin-B or Eph (see Fig. 7A). Furthermore, Fukusumi teaches anti-nephrin and nephrin binds to Ephrin-B1 (see Figs. 7A and 8C), which would read on all the structural limitation of a substance that is antibody. Because Fukusumi’s anti-nephrin read on all the structural limitation of a product claim, anti-nephrin is capable of binding specifically to Ephrin-B or Eph.
With respect to claim 6, Fukusumi teaches dual labeling of immunofluorescence images of Ephrine-B1 (green) and nephrin (red) (see Fig. 7 and pg. 1471, right col., para. 2), would read on a diagnostic reagent having a labeling reagent.
Claims 4-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Takamura et al. (“Partitioning-Defective-6-Ephrin-81 Interaction Is Regulated by Nephrin-Mediated Signal and Is Crucial in Maintaining Slit Diaphragm of Podocyte”, The American Journal of Pathology, vol. 190, no. 2, pgs. 333-346, published 12/16/2019, IDS dated 08/17/2023, cite no. 10).
With respect to claim 4, Takamura teaches Ephrin-B1 plays a critical role at slit diaphragm and nephrotic syndrome model rats were used (see abstract). Figs. 9A-B show that Par-6 and nephrin specifically bind to Ephrin-B1, which would read on a substance that specifically binds to an Ephrin-B.
With respect to claims 5-6, Takamura teaches in Fig. 3A anti-ephrin-B1 antibody (also see caption). Takamura also teaches Western blot in Fig. 3 (caption) which would contain a buffer solution for Western blot. Fig. 5 shows a dual-labeling immunofluorescence (also see caption).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 3-7 are rejected under 35 U.S.C. 103 as being unpatentable over Fukusumi et al. (“Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway”, J. Am. Soc. Nephrol, vol. 29, pgs. 1462-1474, published 2018) in view of Nishi et al. (“Evidence-based clinical practice guidelines for nephrotic syndrome 2014”, Clin Exp Nephrol (2016) vol. 20, pgs. 342-370) and Fehnel et al. et al. (“Dysregulation of the EphrinB2−EphB4 ratio in pediatric cerebral arteriovenous malformations is associated with endothelial cell dysfunction in vitro and functions as a novel noninvasive biomarker in patients”, Experimental & Molecular Medicine (2020), vol 52, pgs. 658–671, published 04/14/2020).
For compact prosecution, the expression level of Ephrin-B is above zero.
With respect to claims 1 and 7, Fukusumi has been discussed above. Fukusumi further teaches in Fig. 1 measuring and assessing Ephrin-B1 and Ephrin-B2 (Fig. 1A) and further measuring proteins in a urinary protein-to-creatinine ratio (Fig. C) (also see caption). Fukusumi teaches compared with controls, ephrin-B1 conditional knockout mice displayed altered podocyte morphology (see abstract under results). Fukusumi further teaches the kidney specimens were obtained from a patient with minimal change nephrotic syndrome treated at the hospital and as a control, we used the normal part of the kidney, obtained via nephrectomy (see pg. 1463, right col., last para. and Fig. 1A-C). Fukusumi teaches Ephrin-B1 staining in podocytes is clearly decreased in a human patient with active nephrotic syndrome (see pg. 1470, right col., para. 2).
However, Fukusumi does not explicitly teach Ephrin-B in urine sample (claim 1) and treating the subject whose expression level of the Ephrin-B exceeds a preset reference value with an effective amount of a compound indicated for treating nephrotic syndrome (claim 7).
Nishi teaches nephrotic syndrome (NS) (see pg. 342, left col. para. 1). Nishi teaches that nephrotic syndrome is a clinical syndrome showing specific features of heavy proteinuria as its consequence (see pg. 345, right col., para. 2). Nishi teaches that the effect of treatment is determined by the urinary protein level after treatment (see pg. 345, right col., bottom of para. 2, and Tables 2-3). Nishi teaches active clinical research on the treatment strategy that focuses on patients with NS using approved immunosuppressive agents (see pg. 345, left col., para. 5 under setting of necessary research themes in the future). Nishi teaches the classification by the response to treatment of nephrotic syndrome with compounds (see pg. 346, Table 3). Nishi teaches heathy persons (see pg. 355, left col., para. 1). Nishi teaches the addition of oral cyclosporine or cyclophosphamide to steroid is effective for the reduction of urinary protein level in frequently relapsing nephrotic syndrome in adults (see pg. 349, right col., para. 1). Nishi teaches at least 1 randomized controlled trial (see pg. 344, left col., para 2).
Fehnel teaches investigating (1) EphrinB2 and EphB4 receptor expression in cerebral AVM and the impact of an altered EphrinB2:EphB4 ratio on brain endothelia cell function (see abstract). Fehnel further teaches the expression of said Ephrin was assessed in urine (by ELSIA) from pediatric patients with AVM and EphrinB2 expression was increased in AVM tissue, which correlated with increased urinary EphrinB2 levels in AVM patients (see abstract). Fehnel also teaches post-treatment urinary EphrinB2 levels normalized in an index patient (see abstract). Fehnel teaches measurement of urinary EphrinB2 demonstrates clinical relevance as a biomarker and levels of EphrinB2 in urine were quantified using ELISA assay and results were normalized to overall urinary protein concentration and compared to levels from control patients (see pg. 663, right col., last para.).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have measured the presence or lack thereof of Ephrin-B in urine sample of Fukusumi because Fukusumi recognizes that the expressions of Ephrin-B1 and nephrin clearly decreased when proteinuria peaked and that the remaining Ephrin-B1 and nephrin were dissociated. In other words, the person would have confirmed whether the presence or lack thereof of the Ephrin-B is in the urine sample because Fukusumi teaches that there is a positive connection and correlation between Ephrin-B and proteinuria (protein in urine).
Additionally, it would have been obvious to have used the anti-Ephrin-B1 antibody for detecting nephrotic syndrome as taught by Fukusumi for measuring Ephrin-B1 in the urine sample Fehnel because Fukusumi teaches that Ephrin-B1 decreases in human patient with active nephrotic syndrome but proteinuria peaked in the urine sample and Fehnel teaches measurement of urinary EphrinB2 demonstrates clinical relevance as a biomarker and levels of EphrinB2 in urine were quantified using ELISA assay and results were normalized to overall urinary protein concentration and compared to levels from control patients. Additionally, it would have been obvious to have treated nephrotic syndrome of Fukusumi with an effective compound as taught by Nishi after comparing with control samples because both Fukusumi and Nishi both recognize subjects with nephrotic syndrome are being treated.
The person would have a reasonable expectation of success in measuring Ephrin-B in urine sample through antibodies because it has been well recognized by Fehnel to quantitate Ephrin-B through antibody detection in urine samples.
With respect to claim 4, Fukusumi teaches nephrin binds to Ephrin-B1 (see Fig. 8C), which reads on a substance that specifically binds to an Ephrin-B. Fukusumi further teaches anti-nephrin, anti-phospho Ephrin-B and anti-Ephrin-B1 would read on the structure of the antibody that binds to Ephrin-B or Eph (see Fig. 7A).
With respect to claim 5, Fukusumi teaches anti-phospho Ephrin-B and anti-Ephrin-B1 would read on the structure of the antibody that binds to Ephrin-B or Eph (see Fig. 7A). Furthermore, Fukusumi teaches anti-nephrin and nephrin binds to Ephrin-B1 (see Figs. 7A and 8C), which would read on all the structural limitation of a substance that is antibody. Because Fukusumi’s anti-nephrin read on all the structural limitation of a product claim, anti-nephrin is capable of binding specifically to Ephrin-B or Eph.
With respect to claim 6, Fukusumi teaches dual labeling of immunofluorescence images of Ephrine-B1 (green) and nephrin (red) (see Fig. 7 and pg. 1471, right col., para. 2), would read on a diagnostic reagent having a labeling reagent.
Conclusion
No claim is allowed.
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/N.P.N/Examiner, Art Unit 1678
/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678