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 .
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on August 20, 2026 has been entered. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any rejections or objections not reiterated herein have been withdrawn.
Applicant's election with traverse of Group I, the combination of miR-100 and S100A8, and administering the selected subject Losmapimod or other selective inhibitor of p38a/3 mitogen-activated protein kinases, antisense oligonucleotides that reduce DUX4 expression, or gene therapy, such as administration of miRNAs directed against DUX4 is reiterated for the record.
Claims 1, 44-50, and 63-74 are currently pending.
Claims 49, 65-67, 69-70, and 74 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected subject matter (a nonelected invention or nonelected species), there being no allowable generic or linking claim.
Claims 1, 44-48, 50, 63-64, 68, and 71-73 have been examined to the extent that the claims read on the elected biomarkers (miR-100 and S100A8). The additionally recited biomarkers have been withdrawn from consideration as being directed to a non-elected invention. Prior to allowance of the claim, any nonelected subject matter that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Claim Rejections - 35 USC § 101
3. 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, 44-48, 50, and 71-72 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims recite a judicial exception that is not integrated into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim analysis is set forth below.
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite abstract ideas.
The claims recite the following limitations:
-A method for detecting or monitoring FSHD (clms 1, 50);
-comparing a quantity of the at least one biomarker in the biological sample from the subject to a control value (clm 1);
-initiating a therapeutic intervention/regimen (clm 1); and
wherein the subject is identified as having severe FSHD miR-100 is increased compared to the control value (clm 50).
The broadest reasonable interpretation of these limitations is that they fall within the mental process groupings of abstract ideas because they cover concepts performed in the human mind, including observation, evaluation, judgment, and opinion.
For examples the steps of detecting/monitoring/identifying could all be accomplished by thinking about the level of the biomarkers. Additionally the comparing step could be accomplished by reading a laboratory report and thinking about whether the level of the biomarkers is increased or decreased. Further the initiating step could be performed by verbally by calling in a prescription or by telling the subject that they should start an intervention/regimen.
The instant claims recite a law of nature.
The claims recite a correlation between biomarkers (miR-100 and S100A8) and FSHD. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Claim 1 recites a step of reducing the severity of FSHD by initiating a therapeutic intervention for FSHD or a therapeutic regimen for FSHD. It is noted that a claim limitation can integrate a judicial exception by applying or using the judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. However the treatment or prophylaxis limitation must be “particular”, i.e., specifically identified so that it does not encompass all applications of the judicial exceptions. Here the therapeutic intervention/regimen is not particular and is instead merely instructions to “apply” the exception in a generic way.
In addition to the judicial exceptions the claims recite steps of collecting a biological sample and detecting miRNA and protein biomarkers in the sample. The steps are not considered to integrate the judicial exception into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exception.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions the claims recite steps of collecting a biological sample and detecting miRNA and protein biomarkers. These steps do not amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
The steps are recited at a high level of generality. Collecting a sample in order to perform tests is well understood, routine, and conventional activity for those in the field of diagnostics. Detecting miRNA and protein biomarkers in a sample merely instructs a scientist to use any detection technique. The claim does not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine, and conventional activities engaged in by scientists prior to applicants invention and at the time the application was filed.
The prior art also demonstrates the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available.
The prior art of Statland (Journal of Neuromuscular Diseases 1 (2014) 181-190) teaches that they performed a prospective cross- sectional study of serum biomarkers in 22 FSHD patients (19 FSHD1, 3 FSHD2) compared to 23 age and gender-matched healthy controls using a commercial multiplex, microsphere-based immune-fluorescent assay of 243 markers. Statland teaches that they identified 7 protein biomarkers: creatine kinase MB fraction (CKMB, 6.52 fold change, P < 0.0001), tissue-type plasminogen activator (PLAT, 1.64 fold change, P < 0.0001), myoglobin (2.23 fold change, P = 0.0001), epidermal growth factor (EGF, 2.33 fold change, P = 0.0004), chemokine (C-C motif) ligand 2 (1.48 fold change, P = 0.0004), CD 40 ligand (1.89 fold change, P = 0.001), and vitronectin (VTN, 1.28 fold change, P = 0.001) (abstract).
Matsuzaka (Environ Health Prev Med (2014) 19:452-458) teaches that they evaluated whether miR-1, miR-133a, and miR-206 can be used as serum biomarkers for muscular dystrophy patients including DMD, myotonic dystrophy 1 (DM1), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSHD), becker muscular dystrophy (BMD), and distal myopathy with rimmed vacuoles (DMRV) by qualitative polymerase chain reaction (PCR) amplification assay. Matsuzaka teaches that the median values of miR-1 levels in the serum of patients with LGMD, FSHD, and BMD were approximately 5.5, 3.3 and 1.7 compared to that in controls, 0.68, respectively (abstract, Fig 1).
Coenen-Stass (Investigation of extracellular microRNAs and Serum Protein Biomarkers in dystrophic Muscle Disease [PhD thesis]. University of Oxford 2016) discloses detection of both miRNA and protein biomarkers in biological samples obtained from subjects with dystrophic muscle disease.
Further it is noted that 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 blood by any means, 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);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Response To Arguments
4. In response the Applicants traversed the rejection under 35 USC 101. The Applicants argue that the rejection should be withdrawn in view of the incorporation of specific treatment step(s) with known FSHD therapeutic regimens or interventions, as well as dependent claims directed to particular modes of therapy, such as administration of Losmapimod. The Applicants argue that the claims as amended do not read on any and every treatment only those known to treat FSHD. Moreover, the claims have been amended to clearly refer to active method steps such as "detecting in the biological sample" or "reducing the severity of FSHD".
This argument and the claim amendments have been fully considered but do not overcome the rejection. First it is noted that the claims as amended recite “initiating” a therapeutic intervention/regimen. The “initiating” step itself is considered to be a judicial exception (mental process step) because initiating a therapeutic intervention could be performed by verbally telling the subject that they should start an intervention/regimen. Even if the claims recited an active process step of “administering” a therapeutic intervention/regimen, the claims would still be rejected because they do not recite a particular treatment. A treatment or prophylaxis limitation must be “particular”, i.e., specifically identified so that it does not encompass all applications of the judicial exceptions. Here recitation of “a therapeutic intervention/regimen” is not particular and is instead merely instructions to “apply” the exception in a generic way. Thus the claims do not recite any steps/elements in addition the judicial exceptions that provide integration into a practical application and the rejection is maintained. It is noted that claims 63-64, 68, and 73 have not been included in the rejection because these claims recite “administering” specific treatments (i.e., an inhibitor of DUX4 expression, an inhibitor of p38α/β mitogen-activated protein kinase, or Losmapimod).
Claim Rejections - 35 USC § 112(b)
5. 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.
Claims 1, 44-48, 50, 63-64, 68, and 71-73 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding Claims 1, 44-48, 50, 63-64, 68, and 71-73 it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites a method for detecting or monitoring Facioscapulohumeral muscular dystrophy (FSHD), yet the method only requires steps of “detecting”, “detecting”, “comparing”, and “reducing”. Thus it is not clear if applicant intends to cover only a method of “detecting”, “detecting”, “comparing”, and “reducing” OR if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the later, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal set forth by the preamble of the claims.
Regarding claims 1, 44-48, 50, 63-64, 68, and 71-73 it is noted that a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 1 recites the broad recitation “biological sample”, and the claim also recites “blood, plasma or serum”, and “saliva, blood, plasma, or serum” which is the narrower statement of the limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. In other words it is unclear if the claims require detecting the biomarkers in a blood, plasma, serum, or saliva sample OR if the biomarkers could be detected in additional sample types, in view of the recitation of “biological sample”. Clarification is required.
Claims 1, 44-48, 50, 63-64, 68, and 71-73 are rejected over the recitation of the phrase “the severity of FSHD” in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claims 1, 44-48, 50, 63-64, 68, and 71-73 are rejected over the recitation of the “detecting in the biological sample at least one other biomarker for FSHD present in the biological sample of the subject”. This recitation is confusing because it is unclear how it relates to the rest of the claim. For example the claims also recite detecting miR-100 and S100A8 and then set forth additional steps to take when these markers are increased in comparison to the control. However the claims do not recite any additional steps to take when the at least one other biomarker for FSHD is increased or decreased in comparison to the control. To the extent that the claims encompass a method wherein only at least one other biomarker for FSHD is detected in the biological sample, it’s unclear if the method just stops after the detection step. Clarification is required.
Regarding claims 46 it is noted that a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 46 recites the broad recitation “biological sample”, and the claim also recites “biofluid or liquid biopsy” which is the narrower statement of the limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. In other words it is unclear if the claims require detecting the biomarkers in a biofluid or liquid biopsy OR if the biomarkers could be detected in additional sample types, in view of the recitation of “biological sample”. Clarification is required.
Claim 47 is rejected over the recitation of the phrase “said blood, plasma, or serum protein biomarkers”. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112(a)
6. 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.
7. Claims 1, 44-48, 50, 63-64, 68, and 71-73 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description rejection.
A. The claims recite the following detection steps:
(i) detecting in a biological sample at least one nucleic acid biomarker from blood, plasma or serum comprising of miR-100, miR-138, miR-486, miR-9, miR-32, miR-146b, miR-92a, miR-576, miR-142-3p, miR-505, miR-29b, miR-32, miR-505, miR-502-3p, miR- 103, miR-98, miR-141, miR-34a, miR-140-3p, miR-329, miR-45 4, miR-95, and/or miR-886- 3p; and/or
(ii) detecting in the biological sample at least one protein biomarker from saliva, blood, plasma or serum comprising S100A8, F13A1, IGF1, PFN1, FBLN1, CFL1, TMSB4X, TPM4, EFEMP1, KRT16, SPP2, PROC, or PRG4; or
(iii) detecting in the biological sample at least one “other” biomarker for FSHD present in the biological sample of the subject (clm 1 and 46).
Regarding (iii), the claims do not set forth what the “other” biomarkers for FSHD are in terms of sufficient relevant identifying characteristics. The recitation of “other” biomarkers could encompass RNA, lncRNA, SNPs, CNVs, epigenetic markers, small molecules etc. The claims encompass measuring a large genus of “other” biomarkers for FSHD that have been identified only in terms of their function.
The specification (para 0122) teaches that sixteen FSHD patients with pediatric onset, matched for sex and age, were selected into two groups of a discovery sample set for circulating biomarker studies: one mild FSHD group (n=8), and one severe FSHD group (n=8), as determined by an FSHD disease severity score. These two groups were each compared to a group of healthy control volunteers (n=8).
The specification (para 0124) teaches that ten miRNAs showed a significant change in expression level in mild FSHD plasma versus healthy controls, and twelve miRNAs showed a significant change in expression level in severe FSHD samples versus controls (Table 2).
The specification (para 0132) teaches that to identify protein candidate biomarkers, we performed LC-MS/MS based proteomic profiling of samples from a discovery group of FSHD patients (Table 3). For this, plasma from FSHD patients (n=25) was compared to healthy volunteer controls (n=17), with a roughly even mix of males and females, and an average age of early- to mid-twenties for each group.
The specification (para 0133) teaches that based on signal intensity, 33 proteins that were significantly different between FSHD and healthy control samples were identified (Table S2).
The specification (para 0134) teaches that to further filter the protein list, unique peptide count data was used to identify proteins that had significantly different counts between FSHD and control samples. This narrowed the candidates down to 14 proteins (Table 4); among these, twelve proteins were higher in FSHD samples versus healthy controls, while two proteins were lower in the FSHD samples versus healthy controls.
The specification provides written description for the miRNA biomarkers in Table 2 and the protein biomarkers in Table S2 and 4. The specification does not describe any other species within the claimed genus to show possession of those species.
Regarding the genus of “other” biomarkers for FSHD, the specification does not describe any structural features of the disclosed biomarkers listed in Tables 2, S2, and 4 that would have been expected to be shared by members of the claimed genus. The specification does not describe any physical and/or chemical characteristics of the disclosed biomarkers listed in Tables 2, S2, and 4 that would be expected to be shared by members of the claimed genus. All members of the genus have the same function, i.e., they are associated with FSHD, but no correlation between their structure and this common function is disclosed. The level of knowledge and skill in the art does not allow those skilled in the art to structurally envisage or recognize additional “other” members of the claimed genus. Because the structure of the species within the claimed genus is expected to vary unpredictably from the structure of the biomarkers listed in Tables 2, S2, and 4, the disclosed biomarkers are not a “representative number” of species within the claimed genus.
Because the FSHD miRNA and protein biomarkers are not representative of the entire claimed genus of “other” biomarkers, and the specification does not disclose structural features shared by members of the genus, the description of the biomarkers listed in Tables 2, S2, and 4 would not have put the applicant in possession of common structural attributes or features shared by members of the genus that structurally distinguish the members of the genus from non-members of the genus at the time of filing. Thus the description of biomarkers listed in Tables 2, S2, and 4 is not sufficient to describe the claimed genus of “other” biomarkers for FSHD. Accordingly, the specification does not provide a representative number of species or sufficient common structural features to show that the applicant would have been in possession at the claimed genus as a whole at the time of filing.
B. The claims recite the following treatment steps:
(i) administering an inhibitor of DUX4 expression (clm 63); and
(ii) administering an inhibitor of p38a/3 mitogen-activated protein kinase (clm 64).
The claimed inhibitors can be an antibody, protein, peptide, small molecule, an inhibitory RNA molecule (e.g., siRNA, shRNA, ribozymes, and antisense oligonucleotides), a vaccine, or a pharmaceutical. The claims encompass administering treatments that have not been defined in terms of their complete structure or any other relevant identifying characteristics.
The specification teaches the following (numbering with respect to the PG-Pub)
[0098] Targeted treatments such as those which reduce DUX4 expression, levels, or toxicity and gene therapy may also be used, such as administration of losmapimod a p38 mitogen-activated protein kinase inhibitor or other such inhibitors which inhibit p38alpha/beta MAPK-mediated signaling. Gene or stem cell therapies may also be employed.
The specification provides written description for losmapimod.
However the specification does not provide written description for ANY inhibitor that reduces DUX4 expression or ANY inhibitor of p38a/3 mitogen-activated protein kinase. The disclosure of the losmapimod is insufficient to demonstrate possession of the genus as a whole.
The breadth of the claims encompasses treatments which the present inventors were not in the possession of, or which were not known to the inventors. The instant disclosure does not allow one of skill in the art to visualize or recognize the structure of these treatments.
For these reasons claims 63 and 64 fail to meet the written description requirement because the claims encompass a significantly large genus of treatments which are not adequately described in the specification.
8. Claims 1, 44-48, 50, 63-64, 68, and 71-73 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 of diagnosing FSHD in a human subject comprising:
(i) detecting the level of miR-100 in a plasma sample obtained from said subject;
(ii) detecting the level of S100A8 protein in the plasma sample obtained from the subject;
(iii) comparing the levels of miR-100 and S100A8 protein in the plasma sample obtained from the subject to the levels of miR-100 and S100A8 protein in plasma samples obtained from control subjects that do not have FSHD; and
(iv) diagnosing the subject as having FSHD when the levels of miR-100 and S100A8 protein are increased in comparison to the levels of miR-100 and S100A8 protein in plasma samples obtained from control subjects that do not have FSHD.
does not reasonably provide enablement for the claims as broadly written. 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/or use the invention commensurate in scope with these claims..
Scope of the Claims/Nature of the Invention
The claims are drawn to a method for detecting or monitoring facioscapulohumeral muscular dystrophy (FSHD) in a human subject.
The claims recite multiple detection steps:
(i) detecting in a biological sample at least one nucleic acid biomarker from blood, plasma or serum comprising of miR-100; and/or
(ii) detecting in the biological sample at least one protein biomarker from saliva, blood, plasma or serum comprising S100A8; or
(iii) detecting in the biological sample at least one “other” biomarker for FSHD present in the biological sample of the subject.
In view of the recitation of the phrase “biological sample” the claims broadly encompass detection of the biomarkers in ANY type of sample (i.e., blood, hair, muscle, brain). Claim 46 is limited to a method wherein the biological sample is a biofluid or liquid biopsy sample. Claim 48 is limited to a method wherein the biological sample is plasma. Claim 72 is limited to a biological sample that comprises urine, sweat, tears, breast milk, bile, interstitial fluid, cytosol, peritoneal fluid, pleural fluid, amniotic fluid, semen, synovial fluid, cerebrospinal fluid (CSF), lymph, mucous, stool or fecal matter, epithelium, hair follicles, mucosal cells or bronchial, nasal, or buccal secretions, cheek swab cells, or a biopsy. Further it is noted that the claims do not set forth what the “other” biomarkers for FSHD are in terms of sufficient relevant identifying characteristics. The recitation of “other” biomarkers could encompass RNA, lncRNA, SNPs, CNVs, epigenetic markers, small molecules etc.
The claims recite a second step of comparing a quantity of the at least one biomarkers in the biological sample from the subject to a control value of a quantity of the biomarker from the same type of sample in an age and gender matched subject who does not have FSHD.
The claims recite a third step of reducing the severity of FSHD in the when miR-100 is increased compared to the control value; and/or reducing the severity of FSHD in the subject FSHD when S100A8 is increased compared to the control value, wherein said reducing the severity of FSHD in the subject comprises initiating a therapeutic intervention for FSHD or a therapeutic regimen for FSHD.
Claim 46 recites further detecting in the biological sample at least one other biomarker for FSHD present in a biofluid or liquid biopsy sample. As discussed above the claims do not set forth what the “other” biomarkers for FSHD are in terms of sufficient relevant identifying characteristics. The recitation of “other” biomarkers could encompass RNA, lncRNA, SNPs, CNVs, epigenetic markers, small molecules etc. Further the claim encompasses the analysis of the biomarker in ANY type of biofluid (i.e., blood, urine, sweat, breast milk, lymph fluid).
The nature of the invention requires a reliable correlation between (i) the level of miR-100 in ANY sample type and FSHD, (ii) the level of S100A8 protein in ANY sample type and FSHD, and (iii) the level of ANY “other” biomarker for FSHD in ANY sample type and FSHD.
Teachings in the Specification and Examples
The specification (para 0122) teaches that sixteen FSHD patients with pediatric onset, matched for sex and age, were selected into two groups of a discovery sample set for circulating biomarker studies: one mild FSHD group (n=8), and one severe FSHD group (n=8), as determined by an FSHD disease severity score. These two groups were each compared to a group of healthy control volunteers (n=8).
The specification (para 0124) teaches that ten miRNAs showed a significant change in expression level in mild FSHD plasma versus healthy controls, and twelve miRNAs showed a significant change in expression level in severe FSHD samples versus controls (Table 2).
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The specification (para 0132) teaches that to identify protein candidate biomarkers, we performed LC-MS/MS based proteomic profiling of samples from a discovery group of FSHD patients (Table 3). For this, plasma from FSHD patients (n=25) was compared to healthy volunteer controls (n=17), with a roughly even mix of males and females, and an average age of early- to mid-twenties for each group.
The specification (para 0133) teaches that based on signal intensity, 33 proteins that were significantly different between FSHD and healthy control samples were identified (Table S2).
The specification (para 0134) teaches that to further filter the protein list, unique peptide count data was used to identify proteins that had significantly different counts between FSHD and control samples. This narrowed the candidates down to 14 proteins (Table 4); among these, twelve proteins were higher in FSHD samples versus healthy controls, while two proteins were lower in the FSHD samples versus healthy controls.
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State of the Art and the Unpredictability of the Art
While methods of measuring biomarkers are known in the art, methods of correlating biomarkers with a phenotype (such as FSHD) are highly unpredictable. The unpredictability will be discussed below.
The claims require detection of “at least one other biomarker for FSHD” present in the biological sample of the subject. The claims do not set forth what the “other” biomarkers for FSHD are in terms of sufficient relevant identifying characteristics. The recitation of “other” biomarkers could encompass RNA, lncRNA, SNPs, CNVs, epigenetic markers, small molecules etc. The claims encompass measuring a large genus of other biomarkers that have been identified only in terms of their function. The specification discloses miRNA biomarkers in Table 2 and protein biomarkers in Table 4 that are differentially expressed in plasma samples obtained from FSHD subjects and healthy controls. The teachings in the specification are not commensurate with the scope of the claims since the claims potentially encompass hundreds of other biomarkers associated with FSHD. In the instant case it is highly unpredictable if other biomarkers exist and could also function in the claimed method. The specification only provides enablement for using the biomarkers disclosed in Table 2 and Table 4.
Because the claims broadly encompass detecting or monitoring FSHD by detecting the level of miR-100, S100A8 protein, and at least one other biomarker for FSHD in ANY type of biological sample, it is relevant to point out that it is highly unpredictable as to whether the results obtained with plasma samples could be extrapolated to other sample types.
The prior art of Mompeon (Scientific Reports March 25, 2020 10:5373) teaches that they conducted a study to see if blood starting material is a source of variance in miRNA profile by performing a paired comparison in plasma and serum of the expression of primary miRNAs associated with CVD. Circulating miRNA yield was similar in both plasma and serum, although a significant increase was observed in patients with Non-ST-elevation myocardial infarction (NSTEMI) compared to control volunteers. When normalized by the expression of miR-484, different patterns of miRNA expression between serum and plasma were observed. Although NSTEMI modified the expression of miR-1 and miR-208 in both serum and plasma, plasma displayed a higher variance than serum (Levene’s test p < 0.01). For miR-133a and miR-26a, differences were only detected in serum (p = 0.0240), and conversely, miR-499a showed differences only in plasma of NSTEMI (p = 0.001). Interestingly, miR-21 showed an opposite pattern of expression, being increased in serum (2−ΔΔCt: 5.7, p = 0.0221) and decreased in plasma (2−ΔΔCt: 0.5, p = 0.0107). Plasma and serum exhibit different patterns of circulating miRNA expression in NSTEMI and suggest that results from studies with different starting material could not be comparable (abstract).
Additionally Armstrong (Molecular Cancer 2015 14:194 ) teaches that they analyzed microRNA of matched FFPE-tumor tissue, plasma, urine exosomes, and WBC’s from patients with bladder cancer. Numerous microRNAs were detected and overlapping from specific bio-specimen sources. MiR-4454 and miR-21 overexpression was found in three sources: tumor, WBCs and urine. Additionally, miR-15b-5p, miR-126-3p, miR-93-5p, and miR-150-5p were common to tumor/WBCs, while miR-720/3007a, miR-205, miR-200c-3p and miR-29b3p common to tumor/urine. Significant associations were noted between the log-adjusted average miRNA counts in tumor vs. WBCs (r = 0.418 p < 0.001), and tumor vs. urine (r = 0.38 p < 0.001). No association was seen tumor vs. plasma exosome miRs (r = 0.07 p = 0.06). Armstrong teaches that microRNA profiling from matched samples in patients shows a significant number of microRNAs up regulated in bladder tumors are identifiable in urine exosomes and WBCs of the same patient, but not in blood plasma (abstract and Fig 2).
In the instant case the inventors only measured miR-100 in plasma samples of subjects with FSHD and healthy individuals. In the absence of evidence to the contrary it is highly unpredictable if the increased expression level of miR-100 in plasma samples from subjects with FSHD in comparison to subjects without FSHD will also be observed in a representative number of additional sample types from those subjects.
The prior art of Corey-Bloom (Int J Mol Sci 21(17), 6363 9/2/2020) teaches that the levels of IL-6 in saliva, but not plasma, correlate with clinical metrics in Huntington’s Disease patients and healthy controls (see title, abstract).
Additionally the prior art of Traxdorf (European Review for Medical and Pharmalogical Sciences 2016 20:4766-4774) teaches that they conducted a study to determine whether serum or saliva S100B could be established as an invasive or non-invasive biomarker of cerebrovascular stress due to chronic intermittent hypoxia in obstructive sleep apnea. Traxdorf teaches that serum S100B was significantly higher in OSA than in healthy control subjects (p=0.007). Values of S100B in saliva showed a marked scatter, so there was no significant difference between the OSA group and controls (p=0.62) (abstract).
In the instant case the inventors only measured S100A8 protein in plasma samples of subjects with FSHD and healthy individuals. In the absence of evidence to the contrary it is highly unpredictable if the increased expression level of S100A8 protein in plasma samples from subjects with FSHD in comparison to subjects without FSHD will also be observed in a representative number of additional sample types from those subjects.
Quantity of Experimentation:
The quantity of experimentation necessary is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able to diagnose or monitor FSHD by detecting increased expression of miR-100 and/or S100A8 protein in ANY type of sample. Additionally the claims encompass being able to diagnose or monitor FSHD based on the detection of ANY “other” biomarker for FSHD.
In order to practice the breadth of the claimed invention one of skill in the art would first have to recruit a large number of subjects with FSHD and a large number of control subjects without FSHD. Then a representative number of different sample types would be needed to be collected from each of the subjects. The samples types would have to be used for expression analysis of miR-100 and S100A8. Then sophisticated analysis would have to be done to determine if miR-100 and S100A8 are increased in a represenative number of different sample types of samples obtained from the FSHD subjects and controls. Further additional experimentation would be necessary to identify “other” biomarkers for FSHD. The specification has merely provided an invitation for further experimentation. The results of such experimentation are highly unpredictable.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue. Attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even “a considerable amount of experimentation is permissible,” as long as it is “merely routine” or the specification “provides a reasonable amount of guidance” regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360-61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is “not without bounds.” Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation “would be excessive, e.g., that it would involve testing for an unreasonable length of time.” 707 F.3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a “diverse and relatively poorly understood group of microorganisms,” with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Additionally, attention is directed to Cephalon at 1823, citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 218 USPQ 961, that work that would require 18 months to 2 years so to enable the full scope of an invention, even if routine, would constitute undue experimentation. As stated therein:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years’ work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] Fed. Cir.1983). (Emphasis added)
Attention is also directed to MPEP 2164.06(b) and In re Vaeck, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Where, as here, a claimed genus represents a diverse and relatively poorly understood group of microorganisms, the required level of disclosure will be greater than, for example, the disclosure of an invention involving a “predictable” factor such as a mechanical or electrical element. See Fisher, 427 F.2d at 839, 166 USPQ at 24.
In view of such legal precedence, the aspect of having to work for so many years just to provide the starting materials for minute fraction of the scope of the claimed invention is deemed to constitute both an unreasonable length of time and undue experimentation.
Conclusions:
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Improper Markush Grouping Rejection
9. Claims 1, 44-48, 50, 63-64, 68, and 71-73 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The claims recite the following Markush groups:
- at least one nucleic acid biomarker from blood, plasma or serum comprising of miR-100, miR-138, miR-486, miR-9, miR-32, miR-146b, miR-92a, miR-576, miR-142-3p, miR-505, miR-29b, miR-32, miR-505, miR-502-3p, miR-103, miR-98, miR-141, miR-34a, miR-140-3p, miR-329, miR-454, miR-95, and/or miR-886-3 (clm 1);
- at least one protein biomarker from saliva, blood, plasma or serum comprising [[of]] S100A8, F13A1, IGF1, PFN1, FBLN1, CFL1, TMSB4X, TPM4, EFEMPI, KRT16, SPP2, PROC, or PRG4 (clm 1);
-at least one nucleic acid biomarker comprising miR-100, miR-29b, miR-34a, miR- 505 or miR-576 (clm 45);
-at least one protein biomarker comprising S100A8, F13A1, IGF1, PFN1, FBLN1, CFL1, TMSB4X, TPM4, EFEMPi, KRT16, SPP2, PROC, or PRG4 (clm 46);
-at least one of miR-100, miR- 32, miR-505, miR-103, miR-98, miR-242, miR-29b, miR-34a, miR-329, miR-454, miR-95 or miR886-3p (clm 50)
These Markush groupings are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
MPEP 2117(II) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)).
MPEP 2117(II) further state that alternatives (1) share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class and (2) share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent in the context of the claimed invention.
MPEP § 2117(II)(A) states that “A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”. Herein the members of the Markush grouping are all gene/proteins. These do not belong to the same recognized physical or chemical class or to the same art-recognized class because there is no expectation from the art that each of the recited genes/proteins would function in the same way in the claimed method. It is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention.
MPEP § 2117(II)(B) states that “Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as explained in subsection IIA above, the members of the Markush grouping may still be considered to be proper where the alternatives share a substantial structure feature that is essential to a common use. Again the members of the Markush grouping are all gene/proteins. While they are all made up of nucleic acids or amino acids, the structure of comprising nucleic acids or amino acids is not essential to any asserted common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response To Arguments
10. In the response the Applicants traversed the Improper Markush group rejection. The Applicants argue that the miRNA biomarkers described in claim 1 share common/similar structures. These miRNAs, as a class, have a well-defined, shared structural scaffold required for their functional activities such as post-transcriptional gene silencing. Furthermore, as a class miRNAs share a common function, namely post-transcriptional gene silencing and mediation of post-transcriptional repression. Applicants argue that the recited protein biomarkers belong to a well- recognized class of biomarkers. Each recited biomarker species is a protein, i.e., a polypeptide composed of amino acids linked by peptide bonds, adopting the conventional protein backbone structure (repeating -NH-CH(R)-CO- units. While these protein biomarkers have differences in their primary structures, this does not render them structurally unrelated in view of their shared peptide backbones necessary to provide a scaffold for biomarker properties associated with their primary and higher order folding structures.
These arguments have been fully considered but are not persuasive. While all miRNAs comprise 21-23 nucleotides, this is not considered to be a substantial structural feature since it is shared by all miRNAs and not unique to those correlated with FSHD. Further the miRNA do not share any common sequences. Although the sequences, like all miRNA sequences, are made up of the same four bases, they do not share any significant similarity in the order in which those bases are arranged. Thus the structures of the miRNAs represented by the sequences are different. Further the examiner acknowledges that the recited proteins are all composed of amino acids. However being composed of amino acids is not considered to be a substantial structural feature since it is shared by all proteins and not unique to those proteins correlated with FSHD. Further the proteins do not share any common amino acid sequences. Although the sequences, like all proteins, are made up of the same amino acids, they do not share any significant similarity in the order in which those amino acids s are arranged. Thus the structures of the proteins represented by the sequences are different. To overcome this rejection it is suggested to limit the independent claims to the elected biomarkers and then recite the non-elected biomarkers in a further dependent claim.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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