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 .
Applicant’s election without traverse of group II, claims 8-14 in the reply filed on 6/25/26 is acknowledged.
Claims 1-7 and 16-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/25/26.
Claims 8-14 are under examination as they read on the elected invention.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 8-14 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.
The instant claims are drawn to a method for identifying cardiac transplant tissue rejection in a human subject, said method comprising:
determining a first immunophenotype profile in an EMB sample taken from said human subject, wherein said first immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31; and
comparing said first immunophenotype profile to a second immunophenotype profile, wherein said second immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31 obtained from EMB samples collected from a human cardiac transplant population that does not have cardiac transplant tissue rejection,
wherein a statistically significant alteration in proportional expression and intensity distribution patterns distributions of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31in said first immunophenotype profile compared to said second immunophenotype profile is indicative of cardiac transplant tissue rejection in said human subject.
Claim 12 is drawn to a method for identifying a subject at risk for future cardiac transplant tissue rejection, said method comprising:
determining a first immunophenotype profile in an EMB sample taken from said human subject, wherein said first immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31; and
comparing said first immunophenotype profile to a second immunophenotype profile,
wherein said second immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31obtained from EMB samples collected from a human cardiac transplant population that does not have cardiac transplant tissue rejection,
wherein a statistically significant alteration in proportional expression and intensity distribution patterns distributions of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31in said first immunophenotype profile compared to said second immunophenotype profile is indicative of increased risk of cardiac transplant tissue rejection in said human subject.
The specification teaches that transplant EMB tissue samples were analyzed. The specification teaches that of the 33 transplant EMB cases, 22 had low ISHLT grades (1R and 0R) and 11 had high ISHLT grades (2R and 3R). Of the cases with low ISHLT grades, 19 had clinically silent rejection and three had clinically evident rejection. Of the cases with high ISHLT grades, seven had clinically evident rejection and four had clinically silent rejection. The specification teaches that high grade EMBs have significantly higher proportions of CD3+ and CD8+ cells than low grade EMBs. The specification teaches that high grade EMBs also have significantly higher proportions of macrophage marker CD68 when compared to low grade EMBs. The specification teaches that clinically silent rejection events have a significantly higher proportion of CD68+ cells than clinically evident rejection events. The specification teaches that cells expressing FoxP3 were twice as abundant in clinically silent rejection, compared to clinically evident rejection both within the low histologic grade and the high histologic grade cohort. The specification teaches PD-L1+ cells were more than four-fold more abundant in clinically silent cases compared with clinically evident cases. The specification teaches that each of the markers (CD8, CD3, CD68, FoxP3, and PD-L1) displayed statistically significant differences between ‘future-rejection’ cases and ‘never-rejection’ cases, as shown in Table 3.
The main issue with regards to the written description provision is that the claims encompass a genus of biomarkers that are not adequately described. The claimed method encompasses determining the protein expression level of the recited markers. The specification teaches that the term "protein" and "polypeptide" are used interchangeably herein when referring to a gene product and fragments thereof and, exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants, fragments, and analogs of the foregoing. These markers or fragments thereof must be detected in an EMB sample of a subject to determine cardiac transplant tissue rejection, and in some embodiments, detection of the markers determines the treatment course of action. However, with the exception of detecting CD8, CD3, CD68, FoxP3, and PD-L1 in EMB samples, there is no indication that the claimed biomarkers or fragments thereof are correlated with cardiac transplant tissue rejection. Moreover, there is no link made between the biomarkers and the treatment to be administered. Thus, the method broadly encompasses detecting any of the claimed biomarkers or fragments thereof and treating the subject with any number of immunosuppressants based upon the detection of the biomarkers or fragments thereof. No description is provided in the specification for determining which treatments would be appropriate for a particular patient based on the biomarker signature, or how the selection of treatment would be affected by the condition. Thus, the specification does not provide adequate guidance regarding how one is to know whether the biomarkers or fragments thereof are predicative of the need for treatment and what treatment to administer. The specification does not fully describe the method or provide any form of standard that would allow the method to achieve the required function. Thus, the methods described by the instant specification encompass overly broad genera, and there is no correlation between the steps of the method and the functional outcome. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. Vas-Catha Inc. V. Mazurka, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The state of the art regarding biomarkers for determining cardiac transplant tissue rejection is discussed by Peyster et al. (JACC Basic Transl Sci. 2020 Apr 1;5(4):328-340). Peyster et al. teach in situ profiling of heart transplant biopsies improves diagnostic accuracy and rejection risk stratification. Peyster et al. teach a method of detecting heart transplant rejection comprising analyzing EMB tissue samples from a subject who has received a transplant from a donor and detecting expression levels of CD3, CD8, CD68, FoxP3, and PD-L1 (See pages 330-332 and tables 2-3). Peyster et al. teach using the marker levels to discriminate between those with future serious rejection and those who never experience serious rejection (See page 337).
van Besouw et al. (Journal of Heart and Lung Transplantation, (JUL 2015) Vol. 34, No. 7, pp. 933-940) teach that endomyocardial biopsies from heart transplant recipients with early or late AR or in an immunologic quiescence period were analyzed for the presence of IL-17 mRNA (See abstract). van Besouw et al. teach that particularly early after heart transplantation, IL-17-producing CD4(+) T cells home to the graft, which contributes to the AR process (See abstract).
Bogdan et al. (ARS Medica Tomitana, (1 Nov 2019) Vol. 25, No. 4, pp. 172-178) discuss the correlations between CD31, CD68, MMP-2 and MMP-9 expression in allograft cardiac rejection. Bogdan et al. evaluated the expression of MMP-2 and-9 and CD31, CD68 (endothelial and histiocytic markers) and the correlations between them using immunohistochemistry, in patients with cardiac allografts (See abstract). Bogdan et al. teach that CD31 and CD68 IR correlated with MMPs IR (especially MMP-9) appear to represent predictive markers for cardiac allograft rejection (See abstract).
Glass et al. (American Journal of Transplantation (2019), 19(11), 3149-3154) teach that CD68/CD31 have increased accuracy in diagnosing pathologic antibody-mediated rejection in cardiac transplant patients (See abstract). Glass et al. teach that twenty-two cardiac transplant endomyocardial biopsies were screened using a CD68/CD31 immunohistochemistry (IHC) double stain. Glass et al. teach that more than one third of patients were overdiagnosed with pAMR using CD68 by IHC alone. We demonstrate the value of using a CD68/CD31 double stain to increase accuracy (See abstract).
Slavinsky et al. (Arkhiv Patologii, (SEP-OCT 2022) Vol. 84, No. 5, pp. 5-10) teach that impaired production of platelet-endothelial cell adhesion molecules (Pecam-1) serves as an early diagnostic marker of heart transplant rejection (See abstract). Slavnisky et al. teach that endomyocardial biopsies of 56 heart transplant recipients were stained with hematoxylin and eosin. Slavinsky et al. teach that the streptavidin-biotin method was used to determine the expression of T-lymphocytes (CD3), B-lymphocytes (CD20), macrophages (CD68) and the C4d component of complement to determine the form and degree of graft rejection (See abstract). Slavinsky et al. teach that the expression of platelet-endothelial cell adhesion molecules PECAM-1 (CD31) was also detected. Slavinsky et al. teach that highest levels of PECAM-1 expression were found in the absence of a heart transplant rejection (See abstract). Slavinsky et al. teach that expression of PECAM-1 reflects the state of the vascular bed of the heart transplant. Its decrease can be considered as an early pathomorphological marker of transplanted heart rejection (See abstract). Slavinsky et al. teach that the expression of CD31 continues to decrease with increasing severity of rejection and is accompanied by the progressive development of necrosis and hemorrhages in the graft heart muscle (See abstract).
Thus, the references above provide examples of potential biomarkers for identifying cardiac transplant tissue rejection; however, the references make clear that no single marker or group of markers is known that is predicative of cardiac transplant tissue rejection. Furthermore, the references do not disclose a correlation between gal-9 and D2-40 and cardiac transplant tissue rejection, as suggested by the specification and claims.
Accordingly, one of skill in the art would need specific guidance when practicing the claimed invention. Applicant has provided little or no descriptive support beyond the mere presentation of generic steps to enable one of ordinary skill in the art to identify which of the claimed biomarkers correlate with cardiac transplant tissue rejection. This is not sufficient to impart possession of the method to Applicant. Even though the specification teaches that some of the markers (i.e., CD8, CD3, CD68, FoxP3, and PD-L1) correlate with cardiac transplant graft rejection in EMB samples, this is not sufficient to impart possession of the entire genus of biomarkers, as the ordinary artisan would not necessarily recognize that other biomarkers of the genus are found in EMB and correlate with cardiac transplant tissue rejection. Although the prior art identifies potential biomarkers for cardiac transplant tissue rejection, some of the biomarkers recited in the instant claims are not recognized by the prior art as being broadly correlated with cardiac transplant tissue rejection. Thus, the prior art does not cure the deficiencies of the specification. Without an adequate description of the claimed method, including specific steps and components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the method as claimed.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech V. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the genus. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester V. G.D. Searle& Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claims 8-14 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 a method for identifying cardiact transplant tissue rejection in a human subject, said method comprising determining a first immunophenotype profiling in an EMB sample taken from said human subject, wherein said first immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL-17, PD-L1, CD4, CD20, CD68, CD86, and CD31, and comparing said first immunophenotype profile to a second immunophenotype profile, wherein said second immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL-17, PD-L1, CD4, CD20, CD68, CD86, and CD31 obtained from EMB samples collected from a human cardiac transplant population that does not have cardiac transplant tissue rejection, does not reasonably provide enablement for all biomarkers encompasses by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability, 5) existence of working samples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
(1) The nature of the invention, (6) Breadth of the claims and (8) Undue experimentation
The nature of the invention is a method for identifying cardiac transplant tissue rejection in a human subject, said method comprising: determining a first immunophenotype profile in an EMB sample taken from said human subject, wherein said first immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31; and comparing said first immunophenotype profile to a second immunophenotype profile, wherein said second immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31 obtained from EMB samples collected from a human cardiac transplant population that does not have cardiac transplant tissue rejection, wherein a statistically significant alteration in proportional expression and intensity distribution patterns distributions of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31in said first immunophenotype profile compared to said second immunophenotype profile is indicative of cardiac transplant tissue rejection in said human subject. Claim 12 is drawn to a method for identifying a subject at risk for future cardiac transplant tissue rejection, said method comprising: determining a first immunophenotype profile in an EMB sample taken from said human subject, wherein said first immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31; and comparing said first immunophenotype profile to a second immunophenotype profile, wherein said second immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31obtained from EMB samples collected from a human cardiac transplant population that does not have cardiac transplant tissue rejection, wherein a statistically significant alteration in proportional expression and intensity distribution patterns distributions of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31in said first immunophenotype profile compared to said second immunophenotype profile is indicative of increased risk of cardiac transplant tissue rejection in said human subject. Therefore, the nature of the invention is a chemical case, wherein there is natural unpredictability in performance of certain species or sub-combinations other than those specifically enumerated; See MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to make and use the claimed method encompassing obtaining an EMB sample and detecting the claimed biomarkers, with a reasonable expectation of success, because it would not be predictable from the disclosure of any particular species what other species may or may not work; See MPEP 2164.03.
The claims broadly encompass determining the protein expression level of the recited markers. The specification teaches that the term "protein" and "polypeptide" are used interchangeably herein when referring to a gene product and fragments thereof and, exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants, fragments, and analogs of the foregoing. Thus, the claims are not only encompass detecting the full-length protein markers recited in the claims, but also fragments of the markers, making the genus encompassed by the claims vast. These markers or fragments thereof must be detected in an EMB sample of a subject to determine cardiac transplant tissue rejection, and in some embodiments, detection of the markers determines the treatment course of action. However, with the exception of detecting CD8, CD3, CD68, FoxP3, and PD-L1 in EMB samples, there is no indication that the claimed biomarkers or fragments thereof are correlated with cardiac transplant tissue rejection. Moreover, there is no link made between the biomarkers and the treatment to be administered. Thus, the method broadly encompasses detecting any of the claimed biomarkers or fragments thereof and treating the subject with any number of immunosuppressants based upon the detection of the biomarkers or fragments thereof. No description is provided in the specification for determining which treatments would be appropriate for a particular patient based on the biomarker signature, or how the selection of treatment would be affected by the condition. Thus, the specification does not provide adequate guidance regarding how one is to know whether the biomarkers or fragments thereof are predicative of the need for treatment and what treatment to administer. The specification does not fully describe the method or provide any form of standard that would allow the method to achieve the required function. Therefore, it would be undue experimentation to determine which biomarkers correlate with cardiac transplant tissue rejection to affect a treatment decision.
(2) The state of the prior art and (4) The predictability or unpredictability of the art
The state of the art regarding biomarkers for determining cardiac transplant tissue rejection is discussed by Peyster et al. (JACC Basic Transl Sci. 2020 Apr 1;5(4):328-340). Peyster et al. teach in situ profiling of heart transplant biopsies improves diagnostic accuracy and rejection risk stratification. Peyster et al. teach a method of detecting heart transplant rejection comprising analyzing EMB tissue samples from a subject who has received a transplant from a donor and detecting expression levels of CD3, CD8, CD68, FoxP3, and PD-L1 (See pages 330-332 and tables 2-3). Peyster et al. teach using the marker levels to discriminate between those with future serious rejection and those who never experience serious rejection (See page 337).
van Besouw et al. (Journal of Heart and Lung Transplantation, (JUL 2015) Vol. 34, No. 7, pp. 933-940) teach that endomyocardial biopsies from heart transplant recipients with early or late AR or in an immunologic quiescence period were analyzed for the presence of IL-17 mRNA (See abstract). van Besouw et al. teach that particularly early after heart transplantation, IL-17-producing CD4(+) T cells home to the graft, which contributes to the AR process (See abstract).
Bogdan et al. (ARS Medica Tomitana, (1 Nov 2019) Vol. 25, No. 4, pp. 172-178) discuss the correlations between CD31, CD68, MMP-2 and MMP-9 expression in allograft cardiac rejection. Bogdan et al. evaluated the expression of MMP-2 and-9 and CD31, CD68 (endothelial and histiocytic markers) and the correlations between them using immunohistochemistry, in patients with cardiac allografts (See abstract). Bogdan et al. teach that CD31 and CD68 IR correlated with MMPs IR (especially MMP-9) appear to represent predictive markers for cardiac allograft rejection (See abstract).
Glass et al. (American Journal of Transplantation (2019), 19(11), 3149-3154) teach that CD68/CD31 have increased accuracy in diagnosing pathologic antibody-mediated rejection in cardiac transplant patients (See abstract). Glass et al. teach that twenty-two cardiac transplant endomyocardial biopsies were screened using a CD68/CD31 immunohistochemistry (IHC) double stain. Glass et al. teach that more than one third of patients were overdiagnosed with pAMR using CD68 by IHC alone. We demonstrate the value of using a CD68/CD31 double stain to increase accuracy (See abstract).
Slavinsky et al. (Arkhiv Patologii, (SEP-OCT 2022) Vol. 84, No. 5, pp. 5-10) teach that impaired production of platelet-endothelial cell adhesion molecules (Pecam-1) serves as an early diagnostic marker of heart transplant rejection (See abstract). Slavnisky et al. teach that endomyocardial biopsies of 56 heart transplant recipients were stained with hematoxylin and eosin. Slavinsky et al. teach that the streptavidin-biotin method was used to determine the expression of T-lymphocytes (CD3), B-lymphocytes (CD20), macrophages (CD68) and the C4d component of complement to determine the form and degree of graft rejection. Slavinsky et al. teach that the expression of platelet-endothelial cell adhesion molecules PECAM-1 (CD31) was also detected. Slavinsky et al. teach that highest levels of PECAM-1 expression were found in the absence of a heart transplant rejection. Slavinsky et al. teach that expression of PECAM-1 reflects the state of the vascular bed of the heart transplant. Its decrease can be considered as an early pathomorphological marker of transplanted heart rejection. Slavinsky et al. teach that the expression of CD31 continues to decrease with increasing severity of rejection and is accompanied by the progressive development of necrosis and hemorrhages in the graft heart muscle (See abstract).
Thus, the references above provide examples of potential biomarkers for identifying cardiac transplant tissue rejection; however, the references make clear that no single marker or group of markers is known that is predicative of all rejection. Furthermore, the references do not disclose a correlation between gal-9 and D2-40 and cardiac transplant tissue rejection, as suggested by the specification and claims.
(5) The amount of direction or guidance provided by the invention; (7) The existence of working examples
The specification teaches that transplant EMB tissue samples were analyzed. The specification teaches that of the 33 transplant EMB cases, 22 had low ISHLT grades (1R and 0R) and 11 had high ISHLT grades (2R and 3R). Of the cases with low ISHLT grades, 19 had clinically silent rejection and three had clinically evident rejection. Of the cases with high ISHLT grades, seven had clinically evident rejection and four had clinically silent rejection. The specification teaches that high grade EMBs have significantly higher proportions of CD3+ and CD8+ cells than low grade EMBs. The specification teaches that high grade EMBs also have significantly higher proportions of macrophage marker CD68 when compared to low grade EMBs. The specification teaches that clinically silent rejection events have a significantly higher proportion of CD68+ cells than clinically evident rejection events. The specification teaches that cells expressing FoxP3 were twice as abundant in clinically silent rejection, compared to clinically evident rejection both within the low histologic grade and the high histologic grade cohort. The specification teaches PD-L1+ cells were more than four-fold more abundant in clinically silent cases compared with clinically evident cases. The specification teaches that each of the markers (CD8, CD3, CD68, FoxP3, and PD-L1) displayed statistically significant differences between ‘future-rejection’ cases and ‘never-rejection’ cases, as shown in Table 3.
(6) Breadth of the claims
Applicant is reminded that carrying out the recitations/limitations in a claim should not be a fishing expedition for a person of ordinary skill in the art. The grant of a patent is premised on this fundamental bargained-for exchange. The inventor must provide a full, complete, and enabling description of the invention and, in exchange, the government provides the inventor with the right to exclude others from practicing the invention. See LizardTech, Inc., v. Earth Res. Mapping, Inc., 424 F-3d 1336,1344 (Fed. Cir. 2005) (describing enablement as an essential part of the patent bargain); in Liebel-Flarsheim Co., v. Medrad., Inc, (Liebel IT) 481 F.3d 1371 (Fed. Cir. 2007) (holding that the claims must enabled the full scope of the broadest claim, even if one or more embodiments are specifically enabled) (at p. 14, last paragraph to page 15, first paragraph of CAFC slip op. 06-1156, 22 March 2007); and AKSteel Corp v. Sollac and Ugine, 344 F.3d 1234, 1343-44 (Fed. Cir. 2003). Moreover, the CAFC has held that claims broad enough to encompass significant nonenabled subject matter will be found nonenabled (Sitrick v. Dreamworks, LLC, 516 F.3d 993 (Fed. Cir. 2008). The holding in Sitrick is a restatement of the precedential CCPA holding in In re Cook and Merigold, 169 USPQ 298 (CCPA 1971) (supra).
In the instant case, no single claim recites all of the steps such that the steps of the claimed method are immediately known or recognizable. The difference in scope between what is claimed and what is taught in the specification and prior art regarding the claimed method of detecting and treating illuminates the fact that the instant claims are a single means claims. A single means claim (i.e. wherein a means recitation does not appear in combination with another recited element of means), is subject to an undue breadth rejection under 35 U.S.C. 112(a). In re Hyatt, 708 F.2d 712, 714-715, 218 USPQ 195,197 (Fed. Cir. 1983) (A single means claim which covered every conceivable means for achieving the stated purpose was held nonenabling for the scope of the claim because the specification disclosed at most only those means known to the inventor.). When claims depend on a recited property, a fact situation comparable to Hyatt is possible, where the claim covers every conceivable structure (means) for achieving the stated property (result) while the specification discloses at most only those known to the inventor. See MPEP 2164.08(a).
Applying the above test to the facts of record, it is determined that 1) no declaration under 37 C.F.R. 1.132 or other relevant evidence has been made of record establishing the amount of experimentation necessary, 2) insufficient direction or guidance is presented in the specification with respect to detecting the genus of biomarkers in EMB samples to determine cardiac transplant tissue rejection, 3) the relative skill of those in the art is commonly recognized as quite high (post-doctoral level). One of skill in the art would require guidance, in order to make or use the method to determine which biomarkers are correlated with cardiac transplant tissue rejection to affect a treatment decision in a manner reasonable in correlation with the scope of the claims. Without proper guidance, the experimentation to is undue.
The Applicant has not provided sufficient guidance to enable one of skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including correlating the biomarkers cardiac transplant tissue rejection to affect a treatment decision. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970). Applicant is reminded that specification does not demonstrate that the biomarkers IL-17, gal-9, CD4, CD20, CD86, D2-40, or CD31 are detected in EMB samples; and further, does not demonstrate that these biomarkers discriminate subjects with a cardiac transplant tissue rejection from those who do not. Without such guidance, determining which biomarkers correlate with cardiac transplant tissue rejection to affect a treatment decision is unpredictable and the experimentation left those skilled in the art is unnecessarily and improperly, extensive and undue. See Amgen Inc v Chugai Pharmaceutical Co Ltd. 927 F 2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991) at 18 USPQ2d 1026-1027 and Exparte Forman, 230 U.S.P.Q. 546(Bd. Pat=. App & int. 1986).
Due to the extreme breadth of the claims, as written, the lack of guidance in the prior art, and the lack of guidance in the specification, one of ordinary skill in the art would have to engage in undue experimentation to make and use the invention of the claims, as written. In view of all of the above, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph.
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 8-14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
The instant claims are drawn to a method for identifying cardiac transplant tissue rejection in a human subject, said method comprising:
determining a first immunophenotype profile in an EMB sample taken from said human subject, wherein said first immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31; and
comparing said first immunophenotype profile to a second immunophenotype profile, wherein said second immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31 obtained from EMB samples collected from a human cardiac transplant population that does not have cardiac transplant tissue rejection,
wherein a statistically significant alteration in proportional expression and intensity distribution patterns distributions of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31in said first immunophenotype profile compared to said second immunophenotype profile is indicative of cardiac transplant tissue rejection in said human subject.
Claim 12 is drawn to a method for identifying a subject at risk for future cardiac transplant tissue rejection, said method comprising:
determining a first immunophenotype profile in an EMB sample taken from said human subject, wherein said first immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31; and
comparing said first immunophenotype profile to a second immunophenotype profile,
wherein said second immunophenotype profile comprises the protein expression levels of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31obtained from EMB samples collected from a human cardiac transplant population that does not have cardiac transplant tissue rejection,
wherein a statistically significant alteration in proportional expression and intensity distribution patterns distributions of CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31in said first immunophenotype profile compared to said second immunophenotype profile is indicative of increased risk of cardiac transplant tissue rejection in said human subject.
The limitations of “determining” and “comparing” under its broadest reasonable interpretation, covers performance of the limitation in the mind. That is, nothing in the claim element precludes the steps from practically being performed in the mind. If a claim limitation, under its broadest reasonable interpretation, covers performance of the limitation in the mind then it falls within the “Mental Processes” grouping of abstract ideas. Accordingly, the limitations of “determining” and “comparing” recite a judicial exception (an abstract idea that falls within the mathematical concept and mental process groupings in the 2019 PEG). In addition, the claim describes the naturally occurring relationship between the recited protein markers and cardiac transplant tissue rejection, and thus is also considered to recite a law of nature. This method describes the correlation of a particular biomarker with a particular condition, which is comparable to concepts identified by the Supreme Court in Mayo. (See Mayo 101 USPQ2d at 1966). Accordingly, the claim recites a judicial exception (both an abstract idea and a law of nature).
This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception. A claim that focuses on the use of a judicial exception must also include additional elements or steps to show that the inventor has practically applied, or added something significant to, the natural principle itself. See Mayo 101 USPQ2d at 1966. Adding steps to a natural biological process or an abstract idea that only recite well-understood, routine, conventional activity previously engaged in by researchers in the field would not be sufficient. See id. At 1966,1970. As stated in MPEP 2106.05(d), the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity. Determining the level of a biomarker in a biological sample by any means has been determined as one of the well-understood, routine, conventional activity: see Mayo, 566 U.S. at 79,101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362,123 USPQ2d 1081,1088 (Fed.Cir. 2017). The claims state the sample is an EMB sample, and state that the immunophenotype is examined using immunocytochemistry, immunoblotting, flow cytometry, or fluorescence-activated cell sorting. Therefore, the additional features of the claims (i.e., examining the immunophenotype in an EMB sample) do not ensure that the claims amount to significantly more than the natural principle itself. The claims use conventional means to observe a natural correlation and therefore, the steps of the claimed methods are not sufficient to transform unpatentable natural correlations into patentable application of those regularities. This is also supported by the findings of the Court in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 115 USPQ2d 1152 (Fed. Cir. 2015), wherein the Federal Circuit held that claims that measure biological substances using methods that are routine and conventional do not amount to more than reliance on a correlation that is a law of nature for patentability. The additional limitation, thus, fails to meaningfully limit the claim because it does not require any particular application of the natural correlation, and is at best the equivalent of merely adding the words "apply it" to the judicial exception. Accordingly, the additional limitations do not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception.
Claims 11 and 14 recite administering a one or more immunosuppressive drugs. 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 specific 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 to comparison into account when deciding treatment making the limitations inclusion in this claim at best nominal. Like the claims in Mayo Collaborative Servs. Prometheus Labs., Inc., 566 U.S. 66, 78 (2013), the claims here tell the relevant audience (doctors) about the law of nature and at most adds a suggestion that the doctors take those laws into account when treating their patients. The limitations of claims 11 and 14 thus fails to meaningfully limit the claim because it does not require any particular application of the recited law of nature, and is at best the equivalent of merely adding the words “apply it” to the judicial exception. Accordingly, the limitations of claims 11 and 14 do not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception.
The question of whether identification of the patient population amounts to significantly more than the judicial exception is addressed in Mayo Collaborative Serv. V. Prometheus Labs., Inc., 566 U.S. 132 S. Ct. 1289, 1293-94, 101 USPQ2d 1961, 1965-66 (2012) (citing Diehr, 450 U.S. at 187, 209 USPQ at 7), when the Supreme Court determined that process claims reciting a correlation may inhibit further discovery by improperly tying up future use of laws of nature, even though the laws of nature at issue are narrow laws that may have limited applications. After measurement of the correlation, the claims can tie up a doctor's subsequent treatment decisions, whether treatment does or does not change in light of inference the doctor has drawn using disclosed correlations, since the claims threaten to inhibit development of more refined treatment recommendations that combine the patentee's correlations with later discovered features, and since the correlation step of the claims is set forth in highly general language covering all processes that make use of the correlation. Further, the steps simply refer to a relevant patient population, which is a pre-existing audience; doctors wish to determine whether a particular patient has a disease, or if the disease has/has not progressed. The claims inform a relevant audience about certain laws of nature; and additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community, and those steps, when viewed as a whole, add nothing significant beyond the sum of the parts taken separately. Even though the laws of nature at issue are narrow laws that may have limited applications, the claim does not amount to significantly more than the natural law itself.
Statement of Relevant Prior Art
Peyster et al. (JACC Basic Transl Sci. 2020 Apr 1;5(4):328-340) teach a method of detecting heart transplant rejection comprising analyzing EMB tissue samples from a subject who has received a transplant from a donor and detecting expression levels of CD3, CD8, CD68, FoxP3, and PD-L1 (See pages 330-332 and tables 2-3). Peyster et al. teach using the marker levels to discriminate between those with future serious rejection and those who never experience serious rejection (See page 337). However, the prior art does not teach or suggest determining the expression CD3, CD8, FoxP3, IL17, PDL1, Gal-9, CD4, CD20, CD68, CD86, D2-40, and CD31 in an EMB sample for detecting cardiac transplant tissue rejection.
Claim Status
No claims are allowed.
Conclusion
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/SANDRA CARTER/ Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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