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 .
Response to Amendment
Claims 1-8 have been amended as requested in the amendment filed on 4 April 2024. Following the amendment, claims 1-10 are pending in the instant application, and are under examination in the instant office action.
Claim Objections
Claims 1-10 are objected to because of the following informalities: the claims contain abbreviations that are not first spelled out. Additionally, claim 9, line 2, “KDa” should be “kDa”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-10 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.
Proper Markush language is finite (“selected from the group consisting of A, B and C”). See MPEP 2173.05(h). Claims 1, 5, 9-10 recite: “selected from among”. This recitation is equivalent to “selected from the group comprising” which is indefinite claim language because it does not clearly set forth whether or not the element reads on only a singular alternative or also encompasses combinations of listed elements. Claims 5 and 9-10 fail to include a conjunction (“and” or “or”), which renders the metes and bounds of the claims further indefinite. This affects all depending claims.
Claim 1 also recites the term “higher molecular weight”, which is a relative term which renders the claim indefinite. While the claim states, “including forms with weight of 39-40 kDa and 45-50 kDa” this does not clearly define the metes and bounds of what is considered “higher”. The term “higher” is not defined by the claim, nor does the specification provide a standard for ascertaining the requisite degree. Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicant may obviate this rejection by using language that limits the molecular weight to within the recited ranges.
Claim 1 is further indefinite wherein it recites: Preparation of the biological sample, Definition of the calibration curve; execution of run and interpolation. The claims fails to set forth those active method steps that are encompassed by, for example, “run”. When read in light of the other claims, “run” can mean running the western assay on cartridges or running the program that interpolates peaks. Therefore, the scope is indefinite. Applicant may obviate this rejection by writing the actual steps required (i.e. wherein preparing said sample comprises desalting by means of disposable salting column) into the independent claim.
Claim 2 and 4 are indefinite because they contain the trademark/trade name Wes®, which is a registered trademark of proteinsimple®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the instant case, proteinsimple® discontinued this service July 30th, 2026. In the present case, the trademark/trade name is used to identify/describe a type of automated Western assay and, accordingly, the identification/description is indefinite.
Claims 9 and 10 both recite, “for use in a method” which is intended use that does not confer any structural, material, or manipulative difference on the scope of the element claimed (modified ProNGF or ProNGF/NGF ratio, respectively). MPEP 2173.05(g) states such language is indefinite if it fails to provide a clear cut indication of the scope of the subject matter covered by the claim; fails to set forth well-defined boundaries of the invention or merely states a problem solved or a result obtained; and fails to convey to one of ordinary skill in the art what structure is encompassed by the claim. This claim fails to meet all (3) criteria set forth in MPEP 2173.05(g) and is rejected.
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 1-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s): a method for providing for the quantification of a biomarker for neurodegenerative pathologies in a fluid that was previously drawn from a patient (claim 1), which is a natural law/phenomenon; claim 9 recites proNGF with post-translational modifications, which is a nature-based product; and claim 10 recites a ratio of ProNGF/NGF; which is an abstract idea mathematical calculation. These judicial exceptions are not integrated into a practical application because the additional elements/steps fail to provide any of the considerations, set forth in MPEP 2106.05(a-c), (e) and (h), that provide for integration. Lastly, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they do not amount to more than what was well-understood, routine and conventional activities in that art at the time.
The claims are directed to statutory categories of invention (STEP 1:YES).
Claims 1-8 are directed to a method for early diagnosis and the monitoring of neurodegenerative pathologies. Diagnosis and monitoring are themselves mental processes and one of the enumerated abstract idea groupings considered judicially excepted subject matter. See MPEP2106.04(a)(III), which defines Mental processes as “concepts performed in the human mind (including an observation, evaluation, judgment, opinion”. The claims further recite a natural correlation/phenomenon/law whereby quantification of a biomarker in a fluid obtained from a patient is correlated to the early diagnosis/monitoring of neurogenerative pathologies. Claim 9 recites a modified ProNGF with post-translational modifications and having a weight of 39-40 kDa or 45-50 KDa, which is a nature-based product. Claim 10 recites a ratio, which is a mathematical concept judicial exception, see MPEP2106.04(a)(I)(B). Therefore the claims recite at least one judicial exception (STEP 2A, Prong One: YES).
According to Step 2A, Prong Two, the claims are next evaluated with respect to whether the judicial exception is integrated into a practical application. This analysis turns to the elements/steps recited in addition to the excepted limitations. Independent claim 1 recites the biomarker for quantification is selected from native proNGF or modified proNGF with weight of 39-40 kDa and 45-50 kDa; NGF; and the proNGF/NGF ratio and the steps are preparation of a fluid biological sample from a patient; definition of the calibration curve; execution of run and interpolation. Depending claims recite 5-8 merely recite the pathology that the method diagnoses/monitors. Claim 2 recites providing that the preparation of the biological sample includes the concentration and desalting of the said CSF, said desalting occurring by means of disposable desalting column, said preparation of the biological sample then providing for the protein precipitation, said precipitation being executed by means of TCA, said sample then being resuspended in 0.1X Simple Wes Buffer, resulting 13 times concentrated, said sample then being admixed with the Master Mix Simple Wes and with 0.1 M DTT, boiled for 5 minutes, aliquoted and preserved at -80°C; said method also providing that the calibration curve is defined with 8 serial dilutions (1:2) of recombinant human proNGF, that the dynamic range is 4000 ng/ml-31 ng/ml, said method providing that the run and interpolation occur by using the Simple Wes.
There are no steps/elements that provide for an integration of the judicial exception into a practical application. The additional steps/elements do not constitute any specific improvement within the technological field. TCA protein precipitation protocols were well-established practices in the art prior to the effective filing date of the application (see Koontz, Methods in Enzymology, 541: 3-10, 2014). Also, the protocol for Simple Western Assay (Claim 2) was well-established before the filing date of the application (see Simple Western Size Assay Development Guide, Revision 1, March 2014). There are no additional elements that reflect an improvement within the technical field; there are no additional elements that apply the natural correlation/phenomena judicial exception to a particular treatment or which utilize a particular machine; there are no additional elements that effect a transformation; and there are no additional elements that apply the judicial exception in some other meaningful way beyond generally linking it to a field, namely, lung injury. In this way the claims, as a whole, amount to nothing more than a drafting effort designed to monopolize the natural correlation itself. ((STEP 2A, Prong Two: NO).
Lastly, the additional steps elements do not add significantly more than what was routine/conventional within the art at the time of filing such that it amounts to significantly more than the judicial exception itself. It was well-established in the art prior to filing that NGF pathways are impaired in neurodegenerative disease pathology such as Alzheimer’s (Bruno et al. Amyloid β-induced nerve growth factor dysmetabolism in Alzheimer disease. Journal of Neuropathology & Experimental Neurology. 2009;68(8):857–69) and Down Syndrome (Iulita et al. Nerve growth factor metabolic dysfunction in Down’s syndrome brains. Brain. 2014). As stated above, the specific steps for TCA protein purification and Simple Wes protein assays were well-established in the art before filing. Therefore, the additionally steps amount to insignificant activity that merely append the judicial exception(s) to a technical field - neurodegenerative pathology. The claimed steps/elements recited in addition to the judicial exception(s), alone or in combination, do not make an inventive contribution over the methods that were known in the art prior to filing, and they amount to mere observation of the natural phenomenon itself, by any means known, with the words “apply it” in order to append it to the field of technology.
As for instant claim 9, which is directed to a modified form of proNGF with post-translational modifications, said modified form having a weight of 39-40 kDa or 45-50 kDa. The following prior art teaches higher molecular weight prepro-NGF exist in nature, particularly as glycosylated NGF prohormone (pg. 2127, last paragraph), either isolated from dorsal root ganglia, or produced by recombinant expression (Reinshagen et al., J Neurochemistry, 74 (5): 2127-2133, 2000).
For all of these reasons, Claims 1-10 are directed to judicially excepted subject matter without significantly more, and the claims are rejected.
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 (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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-6 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Counts et al. Curr Alzheimer Res, 13(7): 800-808, 2016; and Arisi et al., BMC Neurosci., 15: 48, 2014; taken with Koontz, TCA Precipitation, Methods in Enzymology, Vol. 541, 2014; and proteinsimple, Simple Western Size Assay Development Guide (2014).
Regarding claim 1, the Counts et al. prior art teaches methods wherein proNGF is quantified in cerebrospinal fluid comprising preparing the biological sample (pg. 3, Subjects and CSF Sampling). The prior art provides definition of the calibration curve by “Using serial dilutions” of samples (pg. 3, second to last paragraph). Lastly, the prior art teaches the steps of running the assay and providing interpolation analysis (see paragraph bridging pg. 4-5). The prior art teaches detection of proNGF in its forms with higher molecular weight, including forms with weight of 39-40 kDa and 45-50 kDa; NGF, wherein it states, “Membranes were cut at ~50 kDa” (pg. 4, second paragraph); thus, the analysis of the forms would include all forms up to 50 kDa.
Regarding claims 5 and 6, the Counts prior art teaches the CSF samples analyzed are from ventricular CSF was extracted from the posterior ventricle using a 50 ml syringe attached to a 30 gauge needle from 66 participants who were clinically diagnosed within a year of death with no cognitive impairment (NCI), amnesic (aMCI), or mild/moderate AD, which teaches the Alzheimer’s disease of instant claims 5 and 6.
In the Counts reference the samples were previously aliquoted and preserved at -80°C, and providing that the calibration curve comprising serial dilutions, and Counts teaches detection within the range of 8-33 pg/mL, as required by instant claim 2. While the Counts et al. prior art teaches quantifying proNGF and NGF it does not specifically disclose the Simple Wes protocol that is set forth in Claim 2. However, the Koontz prior art and the proteinsimple Simple Western Size Assay Development Guide (hereafter “proteinsimple”) remedy these deficiencies.
Regarding claim 2, the Koonz prior art teaches concentrating and desalting CSF samples by means of precipitation being executed by means of TCA. Specifically step 1A (pg. 7) of Koonz discloses the addition of TCA concentrates a protein. The proteinsimple protocol takes over from there, disclosing the sample is resuspended in 0.1X Simple Wes Buffer (see Example page 11) and then admixed with the Master Mix (pg. 11). Table on page 12 discloses preparing samples using DTT, boiling for 5 minutes (“Heat samples at 95 °C for 5 minutes” of the reference),and then running and interpolating the assay according to the Simple Wes protocol.
Regarding claim 3, the proteinsimple discloses separation of proteins comprising applying voltage across the capillary (“cartridge” of the instant claim; see page 2). The proteinsimple reference provides for separation of proteins over the range of <12 to 230 kDa (see figure 1-2 on page 3).
Regarding claim 4, the proteinsimple reference discloses peaks were obtained as output from the assay (see figure 1-2 on page 3). Digital images are analyzed and quantitated using Compass software which is built into the system (see pg. 2). Since the claimed method reads on the Simple Wes assay, absent evidence to the contrary, it is assumed this teaches “interpolated with a polynomial equation of order 2”, as required by the claim.
It would have been obvious to a person having ordinary skill in the art to use the Simple Western Assay as disclosed by proteinsimple, to quantify NGF and proNGF as taught by the methods of Counts. Explicit motivation to substitute Simple Wes for the ELISA of Counts et al is provided in the proteinsimple reference wherein it states: “Simple Western assays are automated, capillary-based immunoassays. That means no gels, no transfer devices, no blots, no film, and no manual analysis! Just like traditional Western blot analysis, your protein samples are separated, immobilized and probed with target specific antibodies (Figure 1-1). Simple Western systems automate all the steps for you, letting you cut through the variability and straight to highly reproducible quantitation for the proteins in your sample.” Given the guidance and direction in both references, a person having ordinary skill in the art would have been able to predictably quantify proNGF and NGF levels in CSF samples.
While the Counts reference teaches assessing both NGF and proNGF (pg. 4 second and third paragraphs), and Figure 1A discloses a band at around 34 kDa, it does not specifically recite the proNGF/NGF ratio. The Arisi et al. prior art discloses the proNGF/NGF ratios are important.
Regarding claim 10, the Arisi prior art specifically teaches proNGF/NGF seems to partially neutralize the specific effects of the proNGF or NGF individual treatments and demonstrate that the mixture induces gene expression that neither singly produce in PC12 neurons (Abstract). The authors state, “the proNGF/NGF mixture modulates the downstream effect of either neurotrophin form, in ways depending on their ratio, and distinct from NGF and proNGF alone.”
It would have been obvious to a person having ordinary skill in the art, before the effective filing date of the application, to look at the proNGF/NGF levels in the method of Counts et al. Motivation to do so is explicit in the Arisi prior art wherein it teaches the mixture has very different neurotrophic effects than either NGF or proNGF alone. Given the guidance and direction in the Counts prior art, which assesses each (NGF and proNGF) individually, a person having ordinary skill would have been able to determining the ratio of proNGF/NGF with predictable success.
Therefore, the method of the invention is obvious in view of the methods that were disclosed in the art before the filing date of the application, and Claims 1-6 and 10 are rejected.
Conclusion
No claim is allowed.
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/STACEY N MACFARLANE/Examiner, Art Unit 1675
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