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 .
Election/Restrictions
Applicant’s election of NF-L and has-mir-145-5p in the reply filed on 2/23/26 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Status
Claims 16 and 20-21 are cancelled. Claims 1-15 and 17-19 are pending.
Claims 1-15 and 17-19 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statements filed on 8/23/23 have been considered. Signed copies are enclosed.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Objections
Claims 1 and 2 are objected to because of the following informalities: the claims contain initialisms, acronyms and/or abbreviations that should be spelled out upon first occurrence. Appropriate correction is required.
Claims 8, 13, and 19 are objected to because of the following informalities: the “hours” should be specified as “after birth”. For example, the claims should be amended to read “one or more of 24 hours, 48 hours, 96 hours, and 120 hours after birth.” Appropriate correction is required.
Claims 10 and 15 are objected to because of the following informalities: the term “NF-L, Tau” is missing a conjunction. For example, the claims should be amended to read “NF-L [[,]] and Tau” based on the use of the language “group consisting of”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-15 and 17-19 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claims are drawn to a method of diagnosing neonatal encephalopathy (NE) in a patient in need thereof, comprising obtaining at least one blood, plasma, serum, or CSF sample from the patient, detecting the presence and the amount of NE biomarkers GFAP and UCH-L1 in the sample compared to normal control level, determining that the patient has suffered an ischemic event if the amount of the at least one NE biomarker is elevated relative to the control, and optionally administering hypothermic treatment to the patient if an ischemic event is determined. The dependent claims require measuring additional biomarkers such as NF-L, Tau, and miRNAs.
The claims require specific functions, including “determining that the patient has suffered an ischemic event,” without providing the corresponding structure to accomplish that function (i.e. steps). Neither the specification nor the claims set forth means to distinguish NE from another disorder, do not clearly define the patients that are “in need thereof,” and do not set forth specific controls for establishing a threshold to which the levels of the sample can be compared to determine whether a patient has suffered an ischemic event.
The instant specification sets forth an example that examined concentration of serum biomarkers of brain injury in neonates with a low cord pH with or without mild hypoxic-ischemic encephalopathy (see instant specification, example 16). Measurement of GFAP, UCH-L1, NFL and Tau were conducted on blood samples from neonates with a low cord pH with or without evidence of HIE. The study identified “control neonates” for comparison, but the specification does not define the “control neonates”. The example does not set forth definition for controls, thresholds for measurement, or identify other steps (such as measuring cord pH) that would be required to practice the method as claimed.
The instant claims do not fully describe the required method, or present any form of specific threshold or other standards that would allow the method to achieve the required function. The specification provides no specific description of the steps involved, other than a generic introduction of possible assays that may work in the intended method. The specification further does not establish a reasonably specific threshold measurement, or controls for establishing said threshold, that can be used to compare the sample levels for determining a diagnosis. Thus, the method described by the instant specification encompasses an overly broad genus, 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 claims. Vas-Cath Inc. v. Mahurkar, 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 skilled artisan cannot envision the steps, specific assay methods and specific measurement thresholds that are required to establish specific status outcomes. In general, the art regarding establishing biomarkers is unpredictable. Waiker et al (J Am Soc Nephrol. 2012 January; 23(1): 13–21) teach that although diagnostic tests are judged based on their ability to classify individuals according to disease status, the actual disease status is often not known with certainty in clinical medicine. Waiker et al teach that biomarkers may be associated with symptoms or a range of diseases, without being reflective of the specific disease that is claimed (see page 10). It is also important to note that Waiker et al discuss the necessity of specific thresholds. Waiker et al state that tests can result in misclassification of disease status, and this may be specifically due to exclusion of certain intermediate values that may have led to an overestimation of the accuracy of other biomarkers. This indicates that the threshold established for any given biomarker to describe any particular disease is critical for establishing the accuracy of the biomarker to predict disease (see page 8). The disclosure fails to resolve the specific methods, the specific thresholds, or the correlation of ghrelin with any specific disease state. Because the genus may be so highly variant, the examples provided, as well as the generic terms of “risk stratification”, “status of a pneumonia and…heart failure”, "assay method" and “correlation” is insufficient to describe the genus, even when considered in light of the general knowledge in the art.
Further, Mayeux (NeuroRx. 2004 Apr;1(2):182-8) teaches that while biomarkers provide a dynamic and powerful approach to understanding a spectrum of diseases, variability is a major concern in biomarkers (see abstract). Biomarkers are subject to critical timing regarding sample collection, storage conditions, and adequate laboratory handling (see Table 2). Further, normal ranges are often difficult to establish, given interindividual variability, tissue localization, reliability of the biomarker measurements, and persistence of the biomarker (see pages 187-188). This would make comparison to establish disease or select treatment highly unpredictable.
For the specific biomarkers of the instant claims, it is noted that the instant claims require diagnosis of a neonatal encephalopathy without requiring any specific patient, and instead only requires that the patient is “in need thereof”. It is noted that the GFAP and UCH-L1 biomarkers are used to identify a wide range of possible brain injuries. For example, Bazarian et al (Lancet Neurol 2018; 17: 782–89) teaches that GFAP and UCH-L1 can be measured in blood samples to diagnose traumatic intracranial injury (see e.g. abstract). The instant claims do not set forth specific steps, controls, or thresholds to distinguish traumatic brain injury, or any other disorder, from neonatal encephalopathy. In contrast, the teachings of Bazarian suggests that more than one diagnosis could be possible from using the biomarkers of the instant claims. Therefore, the specification does not demonstrate possession of the genus of methods encompassed by the instant claims.
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: …To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the 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 Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-15 and 17-19 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.
Claims 1 and 9 recite “normal control level.” This term is not defined in the specification. The specification recites “normal” as referring to an individual or group of individuals that have not shown any symptoms of NE damage or diseases, and “normal” samples that qualify a sample from a healthy individual. However, there is no identification of a “control level” that would be considered “normal.” It is unclear if the “normal control level” references levels from a single healthy individual, an average level from multiple healthy individuals, or some other measurement.
Claims 1-3 recite the limitation "the at least one NE biomarker". There is insufficient antecedent basis for this limitation in the claim. In fact, the claims recite a specific combination of two biomarkers.
Claim 1, 9, and 14 recite “a patient in need thereof”. However, the specification does not define the criteria that would indicate that a patient is “in need thereof.” Therefore, it is unclear which patients would be eligible for measurement using the claimed methods.
Regarding claims 4 and 11, the claims reference Table 1 from the specification. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)". See MPEP2173.05(s).”
Claim 6 recites “one or more additional miRNA biomarkers that reflect NE/encephalopathy status”. It is unclear what is represented by the slash mark. For example, the base claim recites NE as a specific diagnosis, in contrast to claim 6, which may or may not be reciting NE and encephalopathy as alternatives.
Claim 6 recites “one or more additional miRNA biomarkers that reflect NE/encephalopathy status”. The term “reflect” is not defined in the specification. It is unclear what criteria must be met for the markers to “reflect” disease state, and whether that “reflection” is the same as diagnosis.
Claim 9 recites “based on a deviation”. The term “based on a deviation” is not defined in the specification. It is unclear what criteria must be met for a “deviation” to occur, and what criteria for determination are indicated by the term “based on”.
Claim 9 recites “prognosticating NE patient outcome”. However, this phrase is not defined by the specification, and it is unclear which steps are necessary for said prognosticating, and which outcomes can be expected from the prognostication.
Claim 9 recites both “determining if the NE patients should be treated” and “determining if the NE patients on therapies…are responding to treatment.” These limitations are contradictory. “Determining if the NE patients should be treated” indicates that the patients have not yet been treated, while the “determining if the NE patients on therapies…are responding to treatment” indicates that the patients have already been treated. Therefore, the scope of the patients that are “in need thereof” in the claim is indefinite.
Claim 9 recites “determining the severity of NE,” “determining if the NE patients should be treated” and “determining if the NE patients on therapies…are responding to treatment.” It is unclear what criteria must be met or steps performed to “determine” the severity, treatment administration, or response to treatment.
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 11 recites the broad recitation “one or more miRNAs enumerated in Table 1” , and the claim also recites “optionally wherein the miRNAs are one or more selected from the group consisting of…” which names species also recited in Table 1, and which is the narrower statement of the range/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.
Claim 14 recites “based on the amounts of the NE biomarkers”. The term “based on the amounts of the NE biomarkers” is not defined in the specification. It is unclear what criteria must be met for the “amount of NE biomarkers”, which could represent total concentration level or number of markers measured. If the former is intended, the term “amounts” could represent an average, a total amount, or individual amounts. It is also unclear what criteria for determination are indicated by the term “based on”.
Claim 9 recites “determining that the patient will respond.” It is unclear what criteria must be met or steps performed to “determine” whether the patient will respond.
Claim 17 recites the limitation "the one or more additional biomarkers". There is insufficient antecedent basis for this limitation in the claim.
Claims depending from the rejected claims do not remedy the deficiency and therefore are also rejected.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1, from which claim 3 depends, requires measurement of both GFAP and UCH-L1. However, claim 3 requires only GFAP or UCH-L1. Therefore, claim 3 fails to further limit claim 1, and in fact, improperly broadens the scope of the claims. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-15 and 17-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements, which are recited at a high level of generality, provide conventional assays and samples that do not add meaningful limits to practicing the law of nature and abstract idea.
Based upon an analysis with respect to the claim as a whole, the claims are determined to be directed to a law of nature/natural principle an abstract idea. The instant claims recite a method of diagnosing neonatal encephalopathy (NE) in a patient in need thereof, comprising obtaining at least one blood, plasma, serum, or CSF sample from the patient, detecting the presence and the amount of NE biomarkers GFAP and UCH-L1 in the sample compared to normal control level, determining that the patient has suffered an ischemic event if the amount of the at least one NE biomarker is elevated relative to the control, and optionally administering hypothermic treatment to the patient if an ischemic event is determined. The dependent claims require measuring additional biomarkers such as NF-L, Tau, and miRNAs. The relationship between the recited biomarkers and disease state is a natural principle, which is a judicial exception. This method describes correlation of a particular biomarker with a particular natural disease state, which is comparable to concepts identified by the Supreme Court in Mayo. (see Mayo 101 USPQ2d at 1966). Further, the use of the correlation to determine likelihood of PV progression could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics, or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams).
The Supreme Court in Mayo laid out a framework for determining whether an applicant is seeking to patent a judicial exception itself, or a patent-eligible application of the judicial exception. See Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. 66, 101 USPQ2d 1961). See MPEP 2106. The first step of the analysis asks whether the claimed invention is directed to a statutory category of invention. The instant claims recite a method of diagnosing neonatal encephalopathy (NE) in a patient in need thereof, comprising obtaining at least one blood, plasma, serum, or CSF sample from the patient, detecting the presence and the amount of NE biomarkers GFAP and UCH-L1 in the sample compared to normal control level, determining that the patient has suffered an ischemic event if the amount of the at least one NE biomarker is elevated relative to the control, and optionally administering hypothermic treatment to the patient if an ischemic event is determined. The claim is directed to a method, which is a statutory category of invention.
Second, the claimed invention also must qualify as patent-eligible subject matter, i.e., the claim must not be directed to a judicial exception unless the claim as a whole includes additional limitations amounting to significantly more than the exception (see MPEP 2106). Based upon an analysis with respect to the claim as a whole, the instant claims are determined to be directed to a law of nature/natural principle and an abstract idea. The relationship between the recited biomarkers and diagnosis of NE is a natural principle, which is a judicial exception. This method describes correlation of a particular biomarker with a particular natural disease state, which is comparable to concepts identified by the Supreme Court in Mayo. (see Mayo 101 USPQ2d at 1966). The use of the biomarkers and correlation with disease could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics, or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams). Further, use of a non-linear transformation algorithm and guided auto-encoder to determine a systemic chronic inflammaging score (SCI) are types of activities that have been found by the courts to represent abstract ideas. The Court’s rationale for identifying these "mathematical concepts" as judicial exceptions is that a ‘‘mathematical formula as such is not accorded the protection of our patent laws,’’ Diehr, 450 U.S. at 191, 209 USPQ at 15 (citing Benson, 409 U.S. 63, 175 USPQ 673), and thus ‘‘the discovery of [a mathematical formula] cannot support a patent unless there is some other inventive concept in its application.’’ Flook, 437 U.S. at 594, 198 USPQ at 199. See MPEP 2106.04(a)(2).
Third, a claim that focuses on the use of a natural principle 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 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. The claims identify sample types (e.g. blood, tissue, or combination thereof) for testing, subjects to be tested, and the specification identifies well-known assays for determining protein product expression levels. The identification of sample types and subjects from which the samples are to be collected is routine in the art of medical testing. 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 blood 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). Regarding the possible treatment of the patient, the claims either make the treatment optional, meaning that no treatment is required, or identify a treatment, but do not administer the treatment to all patients tested, which means that some patients will only be tested for diagnosis, but not treated. Therefore, treatment is not required for the methods, and the correlation of biomarkers for diagnosis is the inventive concept. Therefore, the additional features of the claims (i.e., measuring the level of the recited biomarkers, and identifying the source of the sample for screening) 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 applications of those regularities. This is also supported by the findings of the 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 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.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 7-9, 12-14, and 18-19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Douglas-Escobar et al (Front Neurol. 2014 Dec 19; 5:273).
Regarding the limitations of instant claim 1, 9, and 14, Douglas-Escobar measured biomarkers of brain damage in control and hypoxic-ischemic encephalopathy (HIE) neonates (see e.g. abstract). The markers were GFAP and UCH-L1 (see e.g. abstract). Both biomarkers were detectable in cord blood samples from control and HIE neonates (see e.g. abstract). The levels of both biomarkers were elevated in patients with HIE, and evidenced brain damage and later neurodevelopmental outcomes in neonates with HIE (see e.g. abstract). The measurement of the biomarkers is recommended for stratifying responders versus non-responders to hypothermia treatment because there was a rapid decrease in serum concentration of neonates with HIE who had good developmental outcomes (see e.g. page 6, left column, first paragraph, and right column, first two full paragraphs).
Regarding the limitations of instant claim 7, 12 and 18, the samples were taken 0-6 hours after birth (see e.g. page 3, right column).
Regarding the limitations of instant claim 8, 13, and 19, the method can comprise measurement at 24, 48, and 96 h (see e.g. Figure 3).
Claim(s) 1-3, 7, 9-10, 12, 14-15, and 18 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Everett et al (US 2015/0051115 A1; filed 10/27/14; published 2/19/15).
Regarding the limitations of instant claim 1, 9, and 14, Everett measured biomarkers of brain damage in control and hypoxic-ischemic encephalopathy (HIE) neonates (see e.g. abstract and paragraph [0161]). The markers were GFAP (see e.g. paragraphs [0161]-[0162]). Everett also teaches measurement of UCH-L1 as an additional biomarker that can be measured (see e.g. paragraph [0085]). The biomarkers can be measured in cord blood (see e.g. paragraph [0165], [0201], [0207]). The levels were measured and compared to non-neurologically injured controls (see e.g. paragraph [0201]). The measurement of the biomarkers can be used as a diagnostic biomarker for HIE (see e.g. paragraph [0217] and [0221]). The biomarkers correlated with response to treatment, because elevated biomarkers during cooling is significantly associated with evidence of brain injury (see e.g. paragraph [0221]).
Regarding the limitations of instant claim 7, 12 and 18, Everett teaches that the samples were taken 0-6 hours after birth (see e.g. paragraph [0201]).
Regarding the limitations of instant claims 2, 3, 10, and 15 Everett teaches that NF-L can also be measured (see e.g. paragraph [0085]). Claims 10 and 15 lack a conjunction between the term s “NF-L” and “Tau”. However, the language “selected from the group consisting of” indicates that the two biomarkers are Markush group alternatives. Therefore, measurement of either NF-L or Tau reads on the instant claims.
Conclusion
No claim is allowed.
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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674
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