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 .
DETAILED ACTION
Pursuant to a preliminary amendment, claims 1-3, 9, 11, 14, 16 and 22-34 are currently pending in the instant application.
Response to Election/Restriction
Applicant's elected Group I without traverse, claims 1-3, 5 and 8-11 (Applicant states that claims 1-2, 9, 14, 16 and 31-34 are elected), drawn to a multiplexed method for quantitating binding of a test compound to a predetermined target molecule and off-target molecules; and the election of Species as follows:
Species (A): wherein the mixture of target molecules further comprises a heterologous mixture of target molecules (claim 2);
Species (B): where the mixture of target molecules comprises targets that are human target molecules (claim 3);
Species (C): wherein Koff is determined by a displacement method (claim 9);
Species (D) – (F): not elected, in the reply filed on September 23, 2025 is acknowledged.
Claims 22-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 11, 14, 16 and 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
Please Note: in Species (A), Applicant elected the method of claim 1, further comprising wherein the mixture of target molecules further comprises a heterologous mixture of target molecules (claim 2). Amended claim 14 and new claim 34 recite the method of claim 1 further comprising quantitating binding affinity, such that claims 14 and 34 are withdrawn as being directed to a non-elected species. Claim 16 depends from withdrawn claim 14, such that claim 16 is also withdrawn.
The restriction requirement is still deemed proper and is therefore made FINAL.
Therefore, claims 1-3, 9 and 31-33 are under consideration to which the following grounds of rejection are applicable.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on March 9, 2022; December 19, 2022; March 19, 2024; August 16, 2024 and February 13, 2025 have been considered. Initialed copies of the IDSs accompany this Office Action.
The information disclosure statement (IDS) submitted on August 16, 2024 is not in compliance with the provisions of 37 C.F.R. § 1.98(a)(2), which requires a legible copy of each U.S. and foreign patent; each publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed.
The following reference has not been considered by the examiner, as indicated on Form PTO 1449.
Foreign Reference 2: JP2002-355061 of IDS filed on August 16, 2024 has not been considered because and English translation of the document has not been provided.
All other documents in said Information Disclosure Statement were considered as noted by the Examiner initials in the copy attached hereto.
Priority
The present application filed March 9, 2022 is CON of a 35 U.S.C. 371 national stage filing of
International Application No. PCT/EP2020/075250, filed September 9, 2020; which claims the benefit of
European Union Applications EP19306104.1, filed September 13, 2019; and EP19306110.8, filed September 16, 2019.
Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, the as-filed Specification of US Application 17/691,117, filed March 9, 2022, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The specific method steps recited in independent claim 1 does not have support for; “said target molecules are present in the mixture of target molecule that do not exist in nature in same tissue preparation”. Therefore, the priority date for the presently claimed invention is March 9, 2022, the filing date of US Patent Application 17/691,117.
Applicants are invited to specifically indicate the location of the cited phrase pertinent to claim 1 of the instant application.
Claim Objection/Rejections
Claim Interpretation
The term “do not exist in nature in same tissue preparation” in claims 1 and 2 is interpreted to refer to target molecules that are not naturally found in the same tissue preparation, that are not naturally found together in the same tissue preparation, that are not naturally found in a tissue preparation from a healthy subject, that are not naturally found in a tissue preparation of a subject having a particular disease and/or condition, synthetic molecules, and/or are preparatory molecules not naturally found in a tissue preparation (e.g., solvent, buffer, lysis agents, etc.).
Claim Objections
Claims 1 and 2 are objected to because of the following informalities: Claims 1 and 2 recite a mixture of pronouns including “the” and “said” within each claim, such that for consistency, a single pronoun reciting either “the” or “said” should be used.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – New Matter
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 1-3, 9 and 31-33 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description”. According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
The claim contains subject matter that was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art (hereafter the Artisan), that the inventor(s), at the time the application was filed, had possession of the claimed invention. 37 CFR §1.118 (a) states that "No amendment shall introduce new matter into the disclosure of an application after the filing date of the application". Claim 1 recites in part: “said target molecules are present in the mixture of target molecule that do not exist in nature in same tissue preparation” in lines 6-7. Applicant points to paragraphs [0014]; [0018]; and [0027] for where support for the amendments can be found. However, support was not found for this limitation in the as-filed Specification and original claims.
Upon review of the instant as-filed Specification and original claims, support was not found for the plurality of the same functionalized oligonucleotides having the same oligonucleotide structure and the same functionalization in sequential order on the same strand as recited in instant claim 1. The instant as-filed Specification, filed March 9, 2022 teaches, for example; “wherein the target molecules do not exist in a single preparation in nature” (paragraph [0014]); “said target molecules are present in a mixture of receptor target molecules that does not exist in nature” (paragraph [0020]); “wherein the receptor target molecules RT1- RTn are in the mixture not found in nature in a single mixture or in the same tissue” (paragraph [0026]); “a “heterologous mixture of target molecules" refers to a mixture of different target molecules that are not found in nature in a single tissue, or, if present in the same tissue, have different biological functions” paragraph [0059]); and “The binding of a test compound to different target molecules that do not exist together in nature can be carried out simultaneously in a multiplex assay” (paragraph [0062]). No such corresponding teaching of “wherein said target molecules are present in the mixture of target molecule that do not exist in nature in same tissue preparation” is taught by the instant as-filed Specification and/or the original claims.
A claim-by-claim analysis and for dependent claim 1, and a method step by method step analysis regarding where support can be found for the broad teaching “each same functionalized oligonucleotide in a plurality of same functionalized oligonucleotides” in the originally filed specification is respectfully suggested. See MPEP § 2163 particularly § 2163.06.
Claims 1-3, 9 and 31-33 will remain rejected until Applicant cancels all new matter.
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 1-3, 9 and 31-33 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 1 and 2 are indefinite for the recitation of the terms “said target molecules”; “each target molecule” and/or “the target molecules” such as recited in claim 1, lines 6, 9, 14. There is insufficient antecedent basis for the terms “said target molecules”; “each target molecule” and/or “the target molecules” in the claim because claim 1, line 2 recites the term “a predetermined target molecule” and “off-target molecules”, and claim 1, line 4 recites the term “a mixture of target molecules”.
Claim 1 is indefinite for the recitation of the term “do not exist in nature in the same tissue preparation” such as recited in claim 1, line 7 because this limitation is not taught in the as-filed Specification and/or the original claims and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “a plurality of mixtures of ligands” such as recited in claim 1, line 8 because the origin and identity of the plurality of mixtures of ligands is completely unclear. Instant claim 1, line 1-2 recite binding a test compound to a predetermined target molecule, such that the origin and identity of the plurality of mixtures of ligands is confusing and unclear and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “test compounds” such as recited in claim 1, line 9. There is insufficient antecedent basis for the term “test compounds” in the claim because claim 1, line 1 recites the term “a test compound”,
Claim 1 is indefinite for the recitation of the terms “different ligands” and “ligands” such as recited in claim 1, lines 9-10, 12 and 14-15. There is insufficient antecedent basis for the terms “different ligands” and “ligands” in the claim because claim 1, line 8 recites the term “a plurality of mixtures of ligands”.
Claim 1 is indefinite for the recitation of the term “said plurality of mixtures of target molecules” such as recited in claim 1, line 11. There is insufficient antecedent basis for the term “said plurality of mixtures of target molecules” in the claim because claim 1, line 2 recites the term “a predetermined target molecule” and “off-target molecules”, and claim 1, line 4 recites the term “a mixture of target molecules”.
Claims 1 and 31-33 are indefinite for the recitation of the term “step (x)” such as recited in claim 1, lines 15, 18 and 23 because claim 1, line 3 recites the term “the steps of”, but claim 1 does not recite step (a), step (b), etc. and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “the reaction mixture” such as recited in claim 1, lines 15-16. There is insufficient antecedent basis for the term “the reaction mixture” in the claim. Moreover, it is unclear what reaction mixture is being referred to in (e) and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “said binding” in claim 1, line 20 because it is unclear whether the “binding” referred to in line 20 is the target molecules bound to different ligands (claim 1, lines 9-10); or whether the “binding” is the binding measured in (g) (claim 1, line 19) and, thus, the metes and bounds of the claim cannot be determined.
Claims 1 and 9 are indefinite for the recitation of the term “Kon” and “Koff” such as recited in claim 1, line 22 because the terms “K” and/or “Kon” and/or “Koff” are not defined in the claim and, thus, the metes and bounds of the claim cannot be determined.
Claim 2 is indefinite for the recitation of the term “the mixture of different target molecules” such as recited in claim 2, lines 4 and 6. There is insufficient antecedent basis for the term “the mixture of different target molecules” in the claim.
Claim 3 is indefinite for the recitation of the terms “targets” and “human target molecules” such as recited in claim 3, line 2. There is insufficient antecedent basis for the terms “targets” and “human target molecules” in the claim because claim 1, line 2 and 4 recite the term “a predetermined target molecule”, “off-target molecules”; and “a mixture of target molecules”.
Claim 31-33 are indefinite for the recitation of the term “comprises” such as recited in claim 31, line 1 because claims 31-33 depend from instant claim 1, wherein claim 1, lines 3-23 already recite what the method comprises including (a), (b), (c), (d), (e), (f), (g), and (h), such that the method of claim 1 cannot comprise something different in the dependent claims and, thus, the metes and bounds of the claim cannot be determined. The Examiner suggests that Applicant amend the claim 1 to recite, for example, “using a mass spectrometry method” and to amend claim 33 to recite, for example, “wherein the mass spectrometry method is liquid chromatography/electrospray ionization tandem mass spectroscopy”.
Claim 31 is indefinite for the recitation of the terms “said plurality of mixtures” such as recited in claim 312, line 2. There is insufficient antecedent basis for the term “said plurality of mixtures” in the claim because claim 1, line 8 recites the term “a plurality of mixtures of ligands”.
Claim 32 is indefinite for the recitation of the terms “eluting bound ligand from filter” and “concentrating samples from filter” such as recited in claim 32, lines 1-2 because claim 32 depends from claim 1, wherein claim 1 does not recite that any ligands are bound to a filter and/or the presence of any samples and, thus, the metes and bounds of the claim cannot be determined.
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.
Claims 31-33 are rejected under 35 U.S.C. 112(d) 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.
Claims 31-33 recite (in part): “wherein step (x) comprises” in line 1 because claims 31-33 depend from claim 1, wherein claim 1 does not recite step (a), step (b), etc. Additionally, claim 1, lines 3-23 already recite what the method comprises including (a), (b), (c), (d), (e), (f), (g), and (h), such that the method of claim 1 cannot comprise something different in the dependent claims. Thus, claims 31-33 are improper dependent claims 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 32 recites (in part): “wherein step (d) comprises eluting bound ligand from filter using a solvent, then concentration samples from filter using a solvent, then concentrating samples from filter” in lines 1-2, wherein claim 32 depends from claim 1, such that claim 1 does not recite that any ligands are bound to a filter and/or the presence of a sample. Thus, claim 32 is an improper dependent claims 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.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim 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 1-3, 9 and 31-33 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. An analysis with respect to the claims as a whole reveals that they do not include additional elements that are sufficient to amount to significantly more than the judicial exception. See; Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 110 U.S.P.Q.2d 1976 (2014); Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2116, 106 U.S.P.Q.2d 1972 (2013); Mayo Collaborative Svcs. v. Prometheus Laboratories, Inc., 132 S. Ct. 1289, 101 U.S.P.Q.2d 1961 (2012). See also 2014 Interim Guidance on Patent Subject Matter Eligibility, available at http://www.gpo.gov/fdsys/pkg/FR-2014-12-16/pdf/2014-29414.pdf (“2014 Interim Guidance”), and the Office’s examples to be considered in conjunction with the 2014 Interim Guidance in examination of nature-based products, available online at: http://www.uspto.gov/patents/law/exam/mdc_examples_ nature-based_products.pdf (“Nature-Based Products Examples”). This rejection is proper.
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of three issues: (1) whether the claim is directed to one of the four categories recited in §101; (2) whether the claim recites or involves a judicial exception (i.e., a law of nature, natural phenomenon, or natural product); and (3) whether the claim as a whole recites something that amounts to significantly more than the judicial exception. In the instant case, the claims are directed to an abstract idea in the form of quantitating the binding of a test compound. Therefore, they must each be considered to determine whether, given their broadest reasonable interpretation, they amount to significantly more than the judicial exception.
The claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claims as a whole, claims 1-3, 9 and 31-33 do not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
In the instant case, claim 1 is broadly directed to a multiplexed method for quantitating binding of a test compound to a predetermined target molecule and off-target target molecules, comprising the steps of: (a) obtaining a mixture of target molecules from a crude extract from at least one of healthy human tissue, non-healthy human or non-human tissue, and a synthetic protein preparation; (b) incubating the mixture with a plurality of mixtures of ligands and test compounds; (c) removing unbound ligands; (d) isolating ligands bound to test molecules; (e) determining a quantity of ligand bound by the target molecule by measuring ligands obtained in step (d); (f) determining affinity of the test compound for target molecules obtained in step (e); (g) measuring binding of the test compound to the predetermined target molecule, and comparing the binding to off-target molecules; and (h) calculating Kon and Koff for the test compound.
Beginning with Step I of the analysis, which asks whether the claimed invention falls within a statutory category, such that the instant claims are directed to a process, thus, the instant claims are directed to a statutory category. Step I [YES].
Proceeding to Step IIA – Prong One of the analysis, which asks if the claimed invention is directed to a judicial exception, such that claims 1-3, 9 and 31-33 are drawn to an abstract idea in the form mathematical relationships, formulas or equations; generic computers; and/or mental processes in a multiplexed method for quantitating binding of a test compound to a predetermined target molecule and off-target molecules, comprising: obtaining; incubating; removing; isolating; determining a quantity by measuring using mass spectrometry and a calibration curve; determining an affinity of the test compound for the target molecules using data; measuring binding of the test compound to a predetermined target molecule and comparing the binding to binding of the test compound to off-target molecules; and calculating Kon and Koff for the test compound (e.g., mathematical relationships; formulas; equations; the use of a generic computer; calculations; and mental processes).
Thus, the claims recite a natural phenomenon, and an abstract idea, which falls within the groupings of abstract ideas enumerated in the 2019 PEG including encompassing mathematical concepts, equations, and calculations that can be carried out in the human mind, and/or by using a general computer that performs routine and conventional functions, as well as, mental process performed in the human mind including concepts such as observation, evaluation, judgement, and/or opinion. Thus, under the revised Step IIA analysis, the claims are directed to an abstract idea. Step IIA – Prong One [YES].
Step IIA - Prong Two asks whether the claim recites additional elements that integrate the exception into a practical application of the exception. In the instant case, the claims are directed to a judicial exception in the form of a natural phenomenon and an abstract idea. Claim 1 recites:
“(a) obtaining a mixture of target molecules from a crude extract from at least one of (i) healthy or non-healthy human or non-human tissue, and (ii) a synthetic protein preparation, wherein said target molecules are present in the mixture of target molecule that do not exist in nature in same tissue preparation” in lines 4-7; “(e) determining a quantity of ligand that 1v1as bound by the target molecule by measuring ligands that obtained in step (d) at defined time points in the reaction mixture, using mass spectrometry and a calibration curve” in line 14-16; “(f) determining affinity of the test compound for target molecules in said mixture of target molecules using data obtained in step (e)” in lines 17-18; “(g) measuring binding of said test compound to the predetermined target molecule and comparing said binding to binding of said test compound to off-target molecules” in lines 19-20; and “(h) calculating Kon or Koff of the test compound for target molecule using data obtained in step (e)” in lines 22-23. These limitations simply describe a process of collecting and analyzing information, which is analogous to “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)); as well as, “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)). Moreover, many of Applicant’s process steps can be practiced as a mental process performed in the human mind, by pen and paper, or through the use of a generic computer, for example, “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). Hence, these limitations are akin to an “abstract idea itself” which was at issue in Alice Corp. and has been identified among non-limiting examples to be an abstract idea. Additionally, the dependent limitations of claims 2, 3, 9 and 31-33 also suffer from the same issue. In other words, the dependent limitations do not rectify the rejection of the independent claim. By way of example, the limitations of claim 33 recites, “wherein step (e) using mass spectroscopy comprises using liquid chromatography/electrospray ionization tandem mass spectroscopy”, which clearly resembles “organizing information through mathematical correlations” (i.e. Digitech Image Techs., LLC v Electronics for Imaging, Inc., 758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)); and is analogous to “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)); “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)); and “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). Thus, the claims do not integrate the judicial exceptions into a practical application of the exceptions. Step IIA – Prong Two [NO].
Proceeding to Step IIB of the analysis: the question then becomes what element or what combination of elements is sufficient to amount to significantly more than the abstract idea?
The instant independent claim is recited at a high level of generality, such that substantially all practical applications of the judicial exception are covered. For instance, claim 1 is recited without any specificity as to the method of obtaining; the target molecules; the mixture of target molecules; the crude extract; the non-human species; the human and non-human tissues; the health, diseases and/or conditions suffered by the human or non-human; the method or conditions of incubation; the mixtures of ligands; the different ligands; the test compounds; the method of removing unbound ligands; the plurality of mixtures; the method of isolating ligands; the method of determining a quantity of ligand bound by the target; the method of determining affinity; the predetermined target molecules; the off-target molecules; the method of mass spectrometry; the calibration curve produced; the data obtained in step (e); the binding data; the method of measuring binding; the method of comparing binding; the method of calculating Kon and Koff, etc. The claims amount to nothing more than obtaining data; using analytical instruments comprising generic computers, computer programs, algorithms; organizing information through mathematical correlations; obtaining and comparing intangible data including collecting information, analyzing information, and displaying results of an analysis; and/or comparing information regarding a sample or test subject to a control or target data, wherein the steps of the method are well-known, purely conventional or routine in the art.
For example, an MS binding assay addressing the human monoamine transporter (i.e., dopamine transporter, norepinephrine transporter, and serotonin transporter including an LC-MS quantification method for the chosen marker substance is known in the art including a basic workflow for MS Binding Assays comprising: obtaining a tissue preparation; incubation of a target, marker and test compound in a 96-well plate; separation of target-bound markers by vacuum filtration over a 96-well filter plate; liberation of bound marker by elution; and quantification of target-bound marker after liberation by LC-ESI-MS/MS, wherein the results of such kinetic studies can be used to estimate a sufficient incubation time to reach equilibrium of the incubation system, which should be achieved after five times of the dissociation half-life (t1/2) of the target-marker complex, wherein the studies also provide information about the affinity of the marker substance towards the target according to the equation: Kd = koff / kon as evidenced by Grimm (Thesis; pg. 17, first full paragraph; pg. 27, Section 3.2.2; second full paragraph, lines 1-3; and ChemMedChem; pg. 1029, Figure 2). Moreover, a label-free, mass-spectrometry-based binding assays (MS Binding Assays), targeting the human dopamine, norepinephrine, and serotonin transporters (hDAT, hNET, and hSERT) in simultaneous binding experiments were known in the art, wherein LC–ESI-MS/MS was used for quantification of the selective dopamine transporter inhibitor (R,R)-4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidin-3-ol (R,R)-D-84), the selective norepinephrine transporter inhibitor (S,S)-reboxetine, and the selective serotonin reuptake inhibitor (S)-citalopram, binding affinities at the three monoamine transporters could be characterized simultaneously in a single binding experiment by performing simultaneous saturation and competition experiments including simultaneous affinity determination at different targets; and that the workflow includes incubation of three markers with three targets (hDAT, hNET, and hSERT), unbound markers are removed to waste, bound markers are eluted with a solution comprising an internal standard, and samples are analyzed and quantified by LC-ESI-MS/MS and specific binding was calculated as evidenced by Neiens (ChemMedChem, 2018, 13, 453-463; Abstract; pg. 454, Figure 1; and pg.456, col 1, first partial paragraph). Additionally, analysis using multiple MS binding assays for different dopamine receptor subtypes, namely the subtypes D1 and D2, wherein dopamine can be classified into D1 like receptors consisting of the D1 and D5 subtypes as well as D2 like receptors consisting of the D2, D3, and D4 subtypes, respectively; and because dopamine receptors are important targets for the treatment of various dysfunctions, such that dopamine receptor ligands play an important role as established drugs and also as potential drug candidate; and a new LC-ESI-MS/MS method was used to quantify both markers; and Kd values of 0.77 nm and 1.72 nm, for the D1 and the D2 buffer, respectively, were calculated; then nonspecific binding of SCH23390 and raclopride was studied, wherein binding of both markers (at the same concentrations as described above for total binding) in the presence of 10 mm (+)-butaclamol (see Figure 1), a well-known dopamine antagonist with high affinity for both the D1 and the D2 subtype, was thus determined; and the Kd values were calculated for SCH23390 and raclopride was known in the art as evidenced by Schuller (ChemMedChem, 2017, 12, 1585-1594; pg. 1585, col 2, last partial paragraph; pg. 1586, col 1, first partial paragraph; col 2, last partial paragraph; pg. 1589, col 1, first full paragraph; and col 2, last partial paragraph; and pg. 1590, col 1, first partial paragraph). Furthermore, a combination of MS Binding Assays and affinity selection mass spectrometry (ASMS) for library screening was known in the art, wherein the method comprises: (A) Incubation of reporter ligand, target, sub-library to determine the total binding of reporter ligand and library components as well as additionally an excess of competitor ligand for determination of non-specifically bound ligands; (B) Separation of bound from non-bound ligands by vacuum filtration; (C) Liberation of bound ligands with organic solvent and generation of samples for LC-MS analysis; (D) Competitive MS Binding Assay to determine library activity as a function of bound reporter ligand determined by LC-MS; (E) ASMS in the case of active sub-libraries for the identification of the corresponding hits by means of LC-MS quantification of specifically bound library components as a function of total vs. non-specific binding; as well as, evaluation by LC-ESI-MS/MS and determination of Kon and/or Koff as evidenced by Gabriel (Frontiers in Chemistry, 2019, 7:465, 1-18; pg. 5, Figure 1; pg. 6, col 1, first full paragraph; and pg. 7, col 1, first and second full paragraphs). Thus, the claims as a whole simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality to the judicial exception, wherein the steps are well-understood, routine and conventional activities previously known to the industry, as discussed in Alice Corp., 134 S. Ct. at 2359-60, 110 USPQ2d at 1984 (see MPEP § 2106.05(d)). Step IIA [YES].
In sum, when the relevant factors are analyzed, the claims as a whole do NOT recite additional elements that amount to significantly more than the judicial exception itself. Accordingly, claim 1 DOES NOT qualify as eligible subject matter.
Dependent claims 1-3, 9 and 31-33 when analyzed as a whole are held to be patent ineligible under 35 U.S.C. 101 because they do not add anything that makes the natural phenomenon in claim 1, significantly different. For example, claim 33 encompasses the method of claim 1, wherein mass spectrometry is carried out using LC-ESI-MS/MS, but it does not add anything that makes the natural phenomenon and abstract idea in claim 1 significantly different.
In light of the above consideration and the new guidance, claims 1-3, 9 and 31-33 are non-statutory. This rejection is newly recited as necessitated by the new Guidance set forth in the Memorandum of July 30, 2015 updating the June 25, 2014 guidance (see June 25, 2014 memorandum from Deputy Commissioner for Patent Examination Policy Andrew Hirshfeld titled Preliminary Examination Instructions in view of the Supreme Court Decision in Alice Corporation Pty. Ltd. v. CLS Bank International, et al. (Alice Corp. Preliminary Examination Instructions) and the Revised Patent Subject Matter Eligibility Guidance (See, Federal Register, vol. 84, No. 4, January 7, 2019).
Claim Rejections - 35 USC § 103
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 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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 9 and 31-33 are rejected under 35 U.S.C. 103 as being unpatentable over Stephanie Grimm (hereinafter “Grimm”) (Dissertation, Ludwig Maximilain University of Munich, Buchen, Germany, 2015, 1-107; and Publications: Chirality, 2013, 25, 923-933; Analytical Bioanalytical Chemistry, 2015, 407, 471-485; and ChemMedChem, 2015, 10, 1027-1039) in view of Neiens et. al. (hereinafter “Neiens”) (ChemMedChem, 2018, 13, 453-463).
Regarding claim 1, Grimm teaches a comparison between MS binding assays to radioligand binding assays, wherein (1) no labelling of the marker is required for MS binding assays, every native compound is suitable as marker substance as long as it binds with an appropriate affinity towards the target, such that the number of appropriate, commercially available marker substances for the target of interest is therefore significantly higher than for radioligand binding assays; and (2) mass spectrometry allows the simultaneous detection and quantification of several respective [M+H]+ parent ions and the resulting fragment ions), such that different selective ligands can be employed for several target structures in one pot and reliably quantify each individual marker substance in the presence of the other employed marker substances (interpreted as mass spectrometry; and determining a quantity of ligands, claim 1) (pg. 13, last partial paragraph; and pg. 14, first partial paragraph). Grimm teaches developing an MS binding assay addressing the human monoamine transporter (i.e., dopamine transporter, norepinephrine transporter, and serotonin transporter including an LC-MS quantification method for the chosen marker substance (interpreted as human sample; and predetermined target molecule, claims 1 and 3) (pg. 27, Section 3.2.2; second full paragraph, lines 1-3). Grimm teaches two basic requirements for the use of a marker in MS Binding Assays are the following: (1) the marker should possess physicochemical properties that allow good atmospheric ionization, thereby enabling its highly sensitive quantification by LC–ESI-MS/MS; and (2) the marker should exhibit suitable affinity (Kd) for its target, such that the stability of the target–marker complex formed [defined by a sufficiently low dissociation rate constant of the complex (koff) should be high enough to avoid substantial loss of specifically bound marker during separation by filtration and subsequent washing steps, such that the koff of the target-marker should not exceed 10-2 s-1 if the separation step is to be performed by filtration, according to Equation (I): Kd = koff/kon (interpreting separation by filtration as isolating ligands; and interpreting equation (I) as calculating koff and kon, claim 1) (ChemMedChem, pg. 1027, col 2, last partial paragraph; and pg. 1028, col 1, first partial paragraph). Grimm teaches the use of crude animal (rat) brain preparations; and the heterologous expression systems for all three mono-amine transporters that were carried out under consistent conditions, wherein studies are based on brain tissue preparations (interpreted as crude extract from a human/non-human tissue; and heterologous mixture of target molecules, claims 1 and 2) (ChemMedChem; pg. 1029, col 1; first partial paragraph, lines 9-10; and pg. 1034, col 1, first partial paragraph). Grimm teaches in Figure 2, a basic workflow for MS Binding Assays comprising: incubation of a target, marker and test compound in a 96-well plate; separation of target-bound markers by vacuum filtration over a 96-well filter plate; liberation of bound marker by elution; and quantification of target-bound marker after liberation by LC-ESI-MS/MS (interpreted as incubating a mixture of targets molecules; removing unbound ligands; isolating ligands bound to targets; and determining a quantity, claims 1 and 33) (ChemMedChem; pg. 1029, Figure 2). Figure 2 is shown below:
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Grimm teaches a procedure for MS binding experiments, wherein the standard setup for MS binding followed the procedure previously described for MS Binding Assays addressing hNET (See, ref 5b) membrane preparations and marker were incubated in triplicates in the assay buffer in 96-well plates at 37 8C in a shaking water bath for 2 h, wherein incubation was terminated by filtration after transfer of the binding samples (aliquot of 200 mL per well) by means of a 12-channel pipette onto 96-well glass fiber filter plates, which had been pretreated for 1 h with 200 mL of a 0.5% (w/v) polyethyleneimine (PEI) solution; and the membrane fragments with the bound marker remaining on the filer were washed with cold buffer (interpreted as obtaining a tissue extract; incubating targets, ligands and test compounds; removing ligands; isolating ligands; and removing unbound ligand using a glass filter, claims 1 and 31) (ChemMedChem; pg. 1037, col 1; third full paragraph, lines 1-16). Grimm teaches that the affinities (shown as inhibition constant Ki) and the substrate selectivities of the monoamines heavily depend on the targeted transporter, wherein the only really selective transporter is SERT; such that dopamine shows a higher affinity towards NET than the native substrate norepinephrine (Table 1) (interpreted as determining the affinity of test compound for target molecules; a predetermined target molecule; and comparing binding to off-target molecules, claim 1) (pg. 7, last partial paragraph; and Table 1). Table 1 is shown below:
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Grimm teaches that the results of such kinetic studies can be used to estimate a sufficient incubation time to reach equilibrium of the incubation system, which should be achieved after five times of the dissociation half-life (t1/2) of the target-marker complex, wherein the studies also provide information about the affinity of the marker substance towards the target according to the equation: Kd = koff / kon (interpreted as determining affinity; and calculating kon and koff, claim 1) (pg. 17, first full paragraph). Grimm teaches that competitive binding experiments have two main advantages: (1) the affinity of an unknown substance towards a target can be determined without individual quantification methods for each substance; and (2) without time consuming characterization of their Kd-values in separate saturation experiments (interpreted as determining affinity, claim 1) (pg. 19, last full paragraph). Grimm teaches that in the early stages of the development of new anti-depressive drugs a fundamental task is to characterize the affinity of test compounds for targets such as hDAT, hNET, and hSERT; and hat affinities were characterized in saturation experiments using the MS Binding Assays shown in Figure 2 (interpreted as determining affinity, claim 1) (ChemMedChem; pg.1027, col 2, first full paragraph, lines 1-3; and pg. 1029, col 1, last partial paragraph). Grimm teaches that using membrane preparations of HEK293 cells; as well as, brain tissue preparations,rac-(3R,4R)-4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidin-3-ol [rac-(3R,4R)-4] one of the most potent and selective DAT inhibitors described so far, could be confirmed as such, showing high affinity for hDAT (pKi: 7.43) and the highest selectivity for this transporter characterized by a ratio of Ki values of 1:7:36 (hDAT/hNET/hSERT; Table 3); and determination of the affinity of both enantiomers, [(3R,4R)-4] and [(3S,4S)-4] in competitive MS binding assays confirmed that the eutomer, [(3R,4R)-4] possesses even higher selectivity for hDAT (Ki ratios of 1:9:84, hDAT/hNET/hSERT; Table 3) (interpreted as measuring binding to a predetermined target molecules; heterologous; and comparing to off-target binding; and calculating kon and koff, claim 1) (ChemMedChem; pg. 1034, col 1, first partial paragraph; pg. 1035, col 1, last partial paragraph; and col 2, first partial paragraph; and Table 3). Grimm teaches that the determination of Kd values down to 0.40 nM is feasible based on LC-MS quantification of non-labeled marker, such that after characterization of the binding kinetics of (1R,3S)-indatraline toward hDAT, hNET, and hSERT, this stereoisomer was used as a marker in competitive binding experiments, wherein a comprehensive series (nearly 40 compounds) of selective and nonselective inhibitors as well as substrates were assayed for their affinities to all three targets including with respect to affinity, selectivity, and rank order of potency (pg. 1036, col 1, second full paragraph, lines 8-16).
Regarding claim 2, Grimm teaches the use of crude animal (rat) brain preparations; and the heterologous expression systems for all three mono-amine transporters that were carried out under consistent conditions, wherein studies are based on brain tissue preparations; as well as, membrane preparations of HEK293 cells (interpreted as crude extract from a human/non-human tissue; and heterologous mixture of target molecules, claims 1 and 2) (ChemMedChem; pg. 1029, col 1; first partial paragraph, lines 9-10; and pg. 1034, col 1, first partial paragraph).
Regarding claim 3, Grimm teaches that biogenic monoamines dopamine, norepinephrine, and serotonin are important neurotransmitters, which act in the human brain as well as in the periphery (interpreted as human brain, claim 3) (pg. 1, Section 1.1; first partial paragraph, lines 2-3). Grimm teaches developing an MS binding assay addressing the human monoamine transporter (i.e., dopamine transporter, norepinephrine transporter, and serotonin transporter including an LC-MS quantification method for the chosen marker substance (interpreted as human sample; and predetermined target molecule, claims 1 and 3) (pg. 27, Section 3.2.2; second full paragraph, lines 1-3). Grimm teaches employing human embryonic kidney membrane (HEK) preparations (interpreted as human sample, claim 3) (Anal Bioanal Chem; pg. 472, col 2; first partial paragraph, lines 26-27).
Regarding claim 9, Grimm teaches that for hDAT and hSERT, the koff was determined by a dilution approach; and that kinetic experiments were performed using the dilution-based dissociation technique (ChemMedChem; pg. 1031, col 2, first full paragraph; pg. 1032, col 2, first full paragraph; and Figure 5).
Regarding claims 31 and 32, Grimm teaches that membrane preparations and marker were incubated in triplicates in the assay buffer in 96-well plates at 37 8C in a shaking water bath for 2 h, wherein incubation was terminated by filtration after transfer of the binding samples (aliquot of 200 mL per well) by means of a 12-channel pipette onto 96-well glass fiber filter plates, which had been pretreated