DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Office Action: Notice
Any objection or rejection of record in the previous Office Action, mailed 5/8/2025,
which is not addressed in this action has been withdrawn in light of Applicants' amendments
and/or arguments. This action is FINAL.
Claim Status
Claims 1-15, 17-20 and 26 were previously canceled (4/14/2022) and claims 21-22, 32, 38 and 42 are newly cancelled (11/10/2025). Applicant amended claims 16, 23-24, 25, 27-31, 33-37, 39-41 and 43 (11/10/2025). Claims 44-52 are new (11/20/2025). No new matter was added. Thus, claims 16, 23-25, and 27-31, 33-37, 39-41, 43-52 are under examination.
Priority Status
Claims 16, 23-25, and 27-31, 33-37, 39-41, 43-52 receive a US priority date of 12/21/2011, the filing date of US Provisional No. 61/578,344.
Objections/Disclosure Requirements Withdrawn
Specification:
The requirement of a Sequence Disclosure form is withdrawn in view of Applicant’s Request for Transfer of a Computer Readable Form Under 37 CFR 1.821(e) from the parent application 13/721,254.
The objections to the specification due to the use of a trademark or tradenames are withdrawn in view of Applicant’s amendments.
The objections to the specification due to the use of embedded hyperlinks are withdrawn in view of Applicant’s amendments.
Claims:
The minor formality objections to claims 24, 27, and 34 are withdrawn in view of Applicant’s amendments.
New Objections
Claim Objections
Claim 44 is objected to because of the following informality:
Claim 44 at lines 1-2 “a one or more symptoms” should read “one or more symptoms.”
Interpretations Withdrawn
Claim Interpretation – 35 USC § 112(f)
The interpretation of claims 16, 29 and 30 under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier is withdrawn due to Applicant’s amendments of claims 16, 29 and 30 to remove this functional language.
Rejections Withdrawn
Claim Rejections - 35 USC § 112(b)
The rejection of claims 21-22, 32, 38, 42 under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, 2nd paragraph, is withdrawn in view of Applicant’s cancellation of claims 21-22, 32, 38, 42. Further, the rejection of claims 29-31, and 33-37, 39-41 and 43 is withdrawn in view of Applicant’s amendments of instant claims.
Claim Rejections - 35 USC § 112(a)
The rejection of claims 16, 29 and 30 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 is withdrawn in view of Applicant’s amendments of claims 16, 29, and 30 to remove functional language.
Rejections Maintained
Claim Rejections - 35 USC § 112(b)
Claim 28 contains the trademark/trade name Amyvid®. 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 present case, the trademark/trade name is used to identify/describe a radioactive diagnostic agent and, accordingly, the identification/description is indefinite.
Claim 36 contains the trademark/trade name Amyvid®. 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 present case, the trademark/trade name is used to identify/describe a radioactive diagnostic agent and, accordingly, the identification/description is indefinite.
Claim 43 contains the trademark/trade name Amyvid®. 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 present case, the trademark/trade name is used to identify/describe a radioactive diagnostic agent and, accordingly, the identification/description is indefinite.
Applicant’s Response: The Applicant amended claims 28, 36 and 43 to include the trademark symbol following the use of “Amyvid.”
Examiner’s Response to Traversal: Applicant’s arguments have been carefully and fully considered but are not found persuasive, as discussed below.
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).
Claim Rejections - 35 USC § 101
Claims 16, 23-25, and 27-31, 33-37, 39-41 and 43 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
The claims recite method for diagnosing Alzheimer’s-related dementia by measuring biomarkers (Aβ peptides, tau proteins) in patient samples and conducting PET scans. Specifically, the correlation between levels of these naturally occurring biomarkers and the presence/progression of Alzheimer’s disease represents a natural law/phenomenon that exists in nature apart from any human action.
This judicial exception is not integrated into a practical application because the claims merely recite steps of measuring biomarker levels using conventional techniques (multiplexed assay kits) and performing standard PET scans using known radioactive agents (i.e., Pittsburgh Compound B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because measuring autoantibodies to Alzheimer’s-associated proteins and conducting PET scans represent well-understood, routine and conventional activities previously known in the industry. Specifically, when considered separately and in combination, the additional elements of measuring biomarkers using assay kits and conducting PET scans using known agents do not add significantly more to the exception itself and are not markedly different from observing the natural correlation between these biomarkers and Alzheimer’s disease.
Subject Matter Eligibility Test for Products and Processes
Step 1 - Is the Claim to a Process, Machine, Manufacture or Composition of Matter? YES.
The claims provide for methods of diagnosing Alzheimer’s-related dementia (claims 16, 21-25, 27-43). The methods involve measuring biomarker levels in patient samples and conducting PET scans to diagnose Alzheimer’s disease; citing a series of steps.
Thus, the claims are directed to a statutory category (e.g., process).
Step 2A, Prong One — Does the Claim Recite a Product of Nature? YES.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because, whether isolated or not, such naturally-occurring biomarkers (Aβ peptides and tau portions) and the presence/progression of Alzheimer’s disease, are deemed to fall under the judicial exception of natural products, and as such, are not patent-eligible subject matter pursuant to the Supreme Court decision in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 US 66 (2012).
In Mayo, the Court held that “if a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself.” Specifically, the Court held that relationships between concentrations of certain metabolites in the blood and the likelihood that a drug dosage will be ineffective or cause harm are not patent eligible. The correlation between the presence or levels of these biomarkers and Alzheimer’s diseases exists in principle apart from any human action, similar to the correlation at issue in Mayo.
Step 2A, Prong Two — Does the Claim Recite an Additional Elements that Integrate the Judicial Exception into a Practical Application? NO.
The Supreme Court has long distinguished between principles themselves, which are not patent eligible, and the integration of those principles into practical applications, which are patent eligible. However, absent are any additional elements recited in the claim beyond the judicial exceptions which integrate the exception into a practical application of the exception. The “integration into a practical application” requires an additional element or a combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception. The claim limitations “measuring, with a multiplexed assay kit comprising an array of antibodies configured to measure the level of each biomarker or panel,” “conducting a PET scan,” and “diagnosing from said measuring step” are not indicative of integration into a practical application. The above claim limitations are considered simply as the recitation of a naturally-occurring product. Thus, the claims do not provide for any element/step that integrates the law of nature into a practical application.
Step 2B - Does the Claim Recite Additional Elements that Amount to Significantly More than the Judicial Exception? NO.
The Supreme Court has identified a number of considerations for determining whether a claim with additional elements amounts to “significantly more” than the judicial exception(s) itself. The claims as a whole are analyzed to determine whether any additional element/step, or combination of additional elements/steps, in addition to the identified judicial exception(s) is sufficient to ensure that the claim amounts to “significantly more” than the exception(s).
However, the additional elements of the instant application, individually and in combination, do not amount to “significantly more” or “markedly different.” Under the Step 2B analysis, the “physical” elements of the claims are considered to be the same as those found in nature. For example, Andreasen et al. (“CSF markers for Alzheimer's disease: Total tau, phospho-tau and Aβ42”, The World Journal of Biological Psychiatry, published 7/12/2009, from IDS 10/5/2021) discloses that Tau is a normal brain phosphoprotein, which binds to microtubules in the neuronal axon, thereby promoting assembly and stability and exists in six different isoforms in the human brain (Figure 2; p. 148, Paragraph 2). Further, Andreasen discloses that the most commonly used ELISA, INNOTEST™ TAU Ag, for measurement of T-tau in CSF uses monoclonal anti-bodies that detect all isoforms of tau independent of phosphorylation state (Figure 2; p.148, Paragraphs 3-4). High T-tau and low Aβ42 in early Alzheimer’s Disease (AD), but with dementia have been found in several studies suggesting that these markers are positive early in the disease process and the addition of P-tau increases the specificity, since normal P-tau levels are found in most cases with frontotemporal and Lewy body dementia, and also in cerebrovascular disease showcasing that the combination of several of these markers (T-tau, Ab42 and P-tau) will increase the specificity for the diagnosis of AD (Table 4; p. 151, Paragraphs 1-5), thus establishing the natural tendencies used for detection of AD in clinical patients.
Further Du et al. (“Reduced levels of amyloid β-peptide antibody in Alzheimer disease”, Neurology, published 9/11/2001, from IDS 10/5/2021) discloses that senile (neuritic) plaques and neurofibrillary tangles comprise the major neuropathologic features of Alzheimer’s Disease (AD) and are spherical, multicellular lesions that are usually found in moderate to large numbers in limbic structures and association neocortex of AD brain, further comprised of extracellular deposits of amyloid-β peptide(s) (Aβ) that include abundant amyloid fibrils intermixed with nonfibrillar forms of the peptide (Introduction: Paragraph 1). Further, Du discloses that using an ELISA capture assay, anti-Aβ antibody in samples from control subjects who did not have dementia were detected (Figure 1) and further characterized via the specificity of this antibody, using ELISA with protein A agarose (Results: Paragraph 1). Du also discloses that because many of the AD samples investigated in this study have anti-Aβ antibody levels similar to those found in control samples, the role of these antibodies seems unlikely to be primary or at the core of the disease process (Discussion: Paragraphs 1-2) establishing the natural tendencies of Aβ antibodies in AD studies.
Additionally, Herholz et al. (“Clinical amyloid imaging in Alzheimer's disease”, The Lancet Neurology, published 7/2011, from IDS 10/5/2021) discloses a hypothesis that amyloid deposition is the leading cause of Alzheimer's disease (AD) is supported by findings in transgenic animal models and forms the basis of clinical trials of anti-amyloid agents showcasing that amyloid deposition causes severe damage to neurons many years before onset of dementia via a cascade of several downstream effects (Background: Paragraph 1). Further, Herholz discloses that most amyloid imaging in human beings is currently done in research studies with the 11C-labelled PET (Positron emission tomography) tracer PiB (Pittsburgh Compound B); however, the very short physical half-life (20 mins) of 11C requires that a cyclotron be available on-site for production of the isotope, which prevents widespread clinical use since PiB binds to insoluble fibrillary amyloid β with high affinity, but not to amorphous amyloid plaques and neurofibrillary tangles (Pittsburgh Compound B: Paragraph 1). Herholz also discloses that in place of PiB, all three 18F-labelled amyloid ligands undergoing clinical trials could be used to detect fibrillary amyloid in patients with AD with high sensitivity (Conclusions and Future Directions: Paragraph 1), showcasing the widespread use of PiB as a radioactive compounds for usage in PET scans as diagnostic agents for AD patients.
Therefore, the claimed methods for diagnosing Alzheimer’s-related dementia are not deemed to be markedly different than the correlation between biomarkers and disease state found in nature. Simply noting that the method uses a multiplexed assay kit or conducts a PET scan with radioactive diagnostic agents is not sufficient to distinguish the claimed diagnostic methods from the natural correlation between biomarker levels and Alzheimer’s disease.
Thus, when viewed both individually and as an ordered combination, the claimed elements, in addition to the identified judicial exception are found insufficient to supply an inventive concept because the elements are not deemed to be markedly different from those found in nature. Accordingly, the claims do not qualify as patent-eligible subject matter.
Applicant’s Response: The Applicant argues that the claims, as amended, are no longer directed solely to natural correlation between biomarkers and Alzheimer’s disease because they now include an administering step that integrates the diagnostic determination into a practical application. Citing USPTO guidance and Vanda Pharmaceuticals v. West-Ward Pharmaceuticals, the Applicant asserts that the inclusion of a treatment step transforms the claims into patent-eligible methods of treatment rather than ineligible diagnostic claims, therefore amounting to significantly more than a judicial exception.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully and fully considered but are not found persuasive, as discussed below.
Although the amended claims now recite an “administering a treatment regimen” step, the instant claims remain directed to the natural correlation between biomarker levels and Alzheimer’s disease progression. The administering step is generically recited and not tired to a specific therapeutic agent, dosage, or treatment protocol based on a defined biomarker threshold, and therefore amounts to insignificant post-solution activity rather than integration into a practical application. Unlike Vanda, the claims do not require a particularized treatment step that meaningfully limits the judicial exception, and this do not amount to significantly more.
Claim Rejections - 35 USC § 103
Claims 16, 23-25, and 27-31, 33-37, 39-41 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Devanarayan et al. (WO 2011005893 A2; published 1/13/2011) in view of Herholz et al. (“Clinical amyloid imaging in Alzheimer's disease”, The Lancet Neurology, published 7/2011, from IDS 10/5/2021), and in further view of Greenfield et al. (US PGPub 2002/0054870; published 5/9/2002), and Birkett (US PGPub 2003/0138769 A1; published 7/24/2003), and Barghorn et al. (US PGPub 2011/0092445 A1; published 4/21/2011), and Watanabe et al. (US PGPub 2006/0241038 A1; published 10/26/2006), and Bridon et al. (US PGPub 2005/0187159 A1; published 8/25/2005), and Matsuda et al. (US PGPub 2010/0291122 A1; published 11/18/2010), and Chain (US PGPub 2006/0088548 A1; published 4/27/2006), and Krafft et al. (US PGPub 2007/0213512 A1; published 9/13/2007), and Audia et al. (US PGPub 2001/0020097 A1; published 9/6/2001). The rejection has been modified to reflect amendments to the claims (11/10/2025).
Regarding claims 16, 23-25, and 27-31, 33-37, 39-41 and 43, Devanarayan teaches methods for classifying a test sample as indicative of Alzheimer's disease use protein and peptide biomarkers that are differentially expressed in the cerebral spinal fluid (CSF) of subjects with Alzheimer's disease (AD) relative to age-matched controls including protein and peptide signatures indicative of Alzheimer's disease (Abstract). Devanarayan also teaches a kit for classifying a test sample obtained from a human subject, comprising reagents for detecting at least one protein or peptide biomarkers for detecting any one of the protein or peptide biomarker combinations (Tables 2A-4C; p. 4, Paragraph 2). Specifically, Devanarayan teaches that increases in total and p-tau and a concomitant decrease in Aβ l-42 in CSF may be indicative of AD; however, are not specific indicators (p. 1, Paragraph 2). Devanarayan further teaches that these proteins and peptides thus serve as biomarkers for classifying test samples, diagnostics or therapeutic monitoring, either individually or in a panel of biomarkers (p. 11, Paragraph 1).
Devanarayan also teaches another example of indirect labeling, polypeptides capable of specifically binding immunoglobulin constant regions, such as polypeptide A or polypeptide G, can also be used as labels for detection antibodies, which are normal constituents of the cell walls of streptococcal bacteria and can thus be labeled and added to the assay mixture, where they will bind to each capture and detection antibody, as well as to the autoantibodies, labeling all and providing a composite signal attributable to analyte and autoantibody present in the sample (p. 22, Paragraphs 2-3). Specifically, Devanarayan teaches that each primer or probe within the array or kit is capable of specifically hybridizing under stringent conditions to a protein or peptide biomarker (i.e., tau, Aβ peptides) where the different primers or probes may consist of a minimum number of different primers or probes needed to specifically hybridize under stringent conditions to each protein or peptide biomarker (i.e., first or second) and directly correlated with detecting the presence of disease at its earliest stage (Tables 2A, 2B, 3B, 3C, 4B, 4C and 5; p. 24, Paragraph 2).
Further, Devanarayan teaches a method for classifying Alzheimer's disease (AD) state of a subject, comprising: a) selecting a statistically relevant multi-analyte panel from fluid samples obtained from human subjects including a control cohort consisting of healthy subjects and an AD cohort consisting of subjects diagnosed with AD, in which panel a plurality of protein or peptide biomarkers are differentially expressed to provide expression values for a reference AD panel and a control panel; b) conducting a Random Forests or Simulated Annealing analysis on the multi-analyte data from step (a) to derive a signature; c) applying a classification algorithm to the signature of step (b) to refine the signature; d) obtaining a test fluid sample from the subject; e) determining expression level in the test sample for each of the protein biomarkers used to specify the panel of (a); f) providing the results of step (e) to the classification model on the signature obtained from step (c) to obtain an output; and g) determining the classification of the disease state according to the output of step f), wherein the classification is either AD or control (p. 2-3; Paragraph 1). Specifically, Devanarayan teaches that increases in total and p-tau and a concomitant decrease in Aβ l-42 in CSF may be indicative of AD; however, are not specific indicators (p. 1, Paragraph 2).
Devanarayan does not teach or suggest specific sequences disclosed in Aβ 42, 40, 38, 39, 37, 34, 43, 16, 17 or combinations of A-beta peptides as biomarkers. Devanarayan does not teach or suggest the use of a PET scan of a patient’s brain to estimate plaque density in a patient via radioactive diagnostic agent.
Herholz teaches a hypothesis that amyloid deposition is the leading cause of Alzheimer's disease (AD) is supported by findings in transgenic animal models and forms the basis of clinical trials of anti-amyloid agents showcasing that amyloid deposition causes severe damage to neurons many years before onset of dementia via a cascade of several downstream effects (Background: Paragraph 1). Further, Herholz teaches that most amyloid imaging in human beings is currently done in research studies with the 11C-labelled PET (Positron emission tomography) tracer PiB (Pittsburgh Compound B); however, the very short physical half-life (20 mins) of 11C requires that a cyclotron be available on-site for production of the isotope, which prevents widespread clinical use since PiB binds to insoluble fibrillary amyloid β with high affinity, but not to amorphous amyloid plaques and neurofibrillary tangles (Pittsburgh Compound B: Paragraph 1). Further, Herholz teaches that among possible markers of early Alzheimer's disease (AD), the Pittsburgh compound B (PiB) seems to be a sensitive and specific marker of amyloid-β deposition (Herholz: Introduction, Paragraph 1). Herholz also teaches that in place of PiB, all three 18F-labelled amyloid ligands undergoing clinical trials could be used to detect fibrillary amyloid in patients with AD with high sensitivity (Conclusions and Future Directions: Paragraph 1).
Greenfield teaches specified peptide synergism with amyloids and their contribution to Parkinson’s and Alzheimer’s diseases via the calcium channel (Abstract). Further, Greenfield’s artificial peptide sequence, SEQ ID NO. 2 (p. 6), is the same sequence as Aβ16 of the instant application, as shown in Figure 1, below.
PNG
media_image1.png
142
648
media_image1.png
Greyscale
[AltContent: textbox (Figure 1: Greenfield’s SEQ ID NO. 2 is a 100% match to Aβ16 of the instant application. )]
PNG
media_image3.png
122
637
media_image3.png
Greyscale
Birkett teaches stability of self-assembled particles is obtained by the presence of at least one heterologous cysteine residue near the carboxy-terminus of the chimer molecule in relation to the hepatis B virus nucleocapsid protein (Abstract). Further, Birkett’s peptide sequence, SEQ ID NO. 188 (p. 81), is the same sequence as Aβ17 of the instant application, as shown in Figure 2, below.
[AltContent: textbox (Figure 2: Birkett’s SEQ ID NO. 188 is a 100% match to Aβ17 of the instant application. )]
Barghorn teaches specified amyloid β peptide analogues (Abstract). Further, Barghorn’s artificial peptide sequence, SEQ ID NO. 208 (p. 16), is the same sequence as Aβ34 of the instant application, as shown in Figure 3, below.
PNG
media_image4.png
125
679
media_image4.png
Greyscale
[AltContent: textbox (Figure 3: Barghorn’s SEQ ID NO. 208 is a 100% match to Aβ34 of the instant application. )]
PNG
media_image6.png
135
633
media_image6.png
Greyscale
Watanabe teaches specified amyloid β peptide pharmaceutical compositions, specifically Aβ37 (Abstract). Further, Watanabe’s human enzyme sequence, SEQ ID NO. 12 (p. 16), is the same sequence as Aβ37 of the instant application, as shown in Figure 4, below.
[AltContent: textbox (Figure 4: Watanabe’s SEQ ID NO. 12 is a 100% match to Aβ37 of the instant application. )]
PNG
media_image7.png
133
633
media_image7.png
Greyscale
[AltContent: textbox (Figure 5: Bridon’s SEQ ID NO. 1002 is a 100% match to Aβ38 of the instant application. )]Bridon teaches a method for protecting a peptide from peptidase activity in vivo, the peptide being composed of between 2 and 50 amino acids and having a C-terminus and an N-terminus and a C-terminus amino acid and an N-terminus amino acid (Abstract). Further, Bridon’s synthetic peptide sequence, SEQ ID NO. 1002 (p. 13), is the same sequence as Aβ38 of the instant application, as shown in Figure 5, below.
[AltContent: textbox (Figure 6: Matsuda’s SEQ ID NO. 29 is a 100% match to Aβ39 of the instant application. )]
PNG
media_image9.png
133
633
media_image9.png
Greyscale
Matsuda teaches a method for enhancing an immune response and a medicament for preventing or treating Alzheimer disease comprising amyloid β peptide that induces an enhanced immune response (Abstract). Further, Matsuda’s synthetic peptide sequence, SEQ ID NO. 29 (p. 3), is the same sequence as Aβ39 of the instant application, as shown in Figure 6, below.
Chain teaches a chimeric peptide or mixture of chimeric peptides that can be formulated as an immunizing composition and used in a method for immunization of a mammal against an internal peptide (Abstract). Further, Chain’s human enzyme sequence, SEQ ID NO. 2 (p. 11), is the same sequence as Aβ40 of the instant application, as shown in Figure 7, below.
PNG
media_image10.png
155
635
media_image10.png
Greyscale
[AltContent: textbox (Figure 7: Chain’s SEQ ID NO. 2 is a 100% match to Aβ40 of the instant application. )]
Krafft teaches specified amyloid β peptides for the assembly of vaccines (Abstract). Further, Krafft’s artificial polypeptide sequence, SEQ ID NO. 5 (p. 5), is the same sequence as Aβ42 of the instant application, as shown in Figure 8, below.
PNG
media_image12.png
129
684
media_image12.png
Greyscale
[AltContent: textbox (Figure 8: Krafft’s SEQ ID NO. 5 is a 100% match to Aβ42 of the instant application. )]
Audia compounds which inhibit β-amyloid peptide release and/or its synthesis, which
PNG
media_image14.png
141
635
media_image14.png
Greyscale
[AltContent: textbox (Figure 9: Audia’s SEQ ID NO. 1 is a 100% match to Aβ43 of the instant application. )]and, accordingly, have utility in treating Alzheimer's disease (Abstract). Further, Audia’s precursor protein SEQ ID NO. 1 (p. 7), is the same sequence as Aβ43 of the instant application, as shown in Figure 9, below.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Devanarayan’s biomarker panel approach with Herholz’s PET-scanning technique to create a more comprehensive diagnostic method for Alzheimer’s disease. This combination would provide complementary diagnostic information: biomarker measurements indicating molecular changes associated with AD and PET imaging directly visualizing amyloid plaque deposits in the brain. Further, the specific biomarkers claimed (Aβ16, 17, 43, 34, 37, 39, 38, 40 42 and total-tau, P-tau and C-tau) would have been obvious to include based on the teachings of Greenfield, Barghorn, Watanabe, Bridon, Matsuda, Birkett, Chain, Audia and Krafft, which collectively suggest the diagnostic value of these specific biomarkers. Further, the motivation to combine these references is further supported by the recognized need in the art for more accurate early diagnosis of AD. For example, Devanarayan teaches that biomarkers can be used for early detection of AD and Herholz further emphasize that amyloid decomposition occurs many years before onset of dementia, suggesting the value of combining different diagnostic approaches for earlier and more accurate detection.
A person of ordinary skill in the art would have had a reasonable expectation of success in combining these prior art elements due to both biomarker measurement techniques and PET scanning being well-established in relation to tracing and scanning for β-amyloids. Further, a correlation between the two technique was well-established at the time of the invention, since Herholz teaches that PET imagining can reliably detect amyloid plaques and Devanarayan teaches that changes in tau and Aβ levels are indicative of AD for diagnostic purposes.
Specifically, both techniques, as well as the teachings of Greenfield, Barghorn, Watanabe, Bridon, Matsuda, Birkett, Chain, Audia and Krafft for the specified sequences, provide specific technical details that would enable one skilled in the art to implement the combined method. For example, Greenfield provides the exact sequence of Aβ16, within the same context of amyloids and their contribution to Parkinson’s and Alzheimer’s diseases, as both Herholz and Devanarayan. Therefore, the combination of Devanarayan’s biomarker approach with Herholz’s imaging technique, along with the specific biomarkers taught by additional references, would have been obvious through routine optimization and testing of known Alzheimer’s related peptides.
Applicant’s Response: The Applicant argues that the cited references, alone or in combination, do not teach or suggest the claimed multi-step method requiring measurement of specific Aβ biomarkers, assessment of neurophysiological symptoms or PET-based plaque estimation, and reliance on all steps to determine Alzheimer’s disease and administer a treatment regimen. Applicant contends that Devanarayan does not disclose the specific Aβ peptide sequences recited nor the use of PET imaging to estimate plaque density, and that the secondary references fail to render the specific biomarker combinations obvious.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully and fully considered but are not found persuasive, as discussed below.
Devanarayan teaches classification of Alzheimer’s disease using panels of protein and peptide biomarkers, including Aβ species and tau markers, and contemplates use of such biomarkers individually or in panels for diagnosis and therapeutic monitoring (see Tables 2A-4C; p. 11). While Devanarayan does not teach each specific Aβ fragment verbatim, the secondary references (Greenfield, Barghorn, Watanabe, Bridon, Matsuda, Birkett, Chain, Krafft, and Audia) collectively teach the specific Aβ peptide sequences recited, establishing that the selection of particular known Aβ fragments from a recognized pool of AD-associated biomarkers constitutes routine optimization of result-effective variables (see MPEP 2144.05 as optimization of known parameters is ordinarily obvious).
Further, Herholz teaches PET imaging using amyloid-binding radiotracers to estimate plaque burden in the brain and emphasizes its diagnostic value in Alzheimer’s disease (Pittsburgh Compound B: Paragraph 1). A person of ordinary skill in the art would have been motivated to combine Devanarayan’s biomarker panel approach with Herholz’s PET imaging to obtain complementary molecular and imaging data for improved diagnostic accuracy, consistent with the recognized need for earlier and more reliable AD detection (see MPEP 2143 for rationale to combine for predictable results).
The Applicant’s argument that no single reference discloses all limitations is unpersuasive because the rejection is based on a combination of references (see MPEP 2141 and In re Keller, 642 F. 2d 413 (CCPA 1981)), and nonobviousness cannot be established by attacking references individually where the rejection is based on a combination. Further, the recited administering a treatment regimen step is broadly stated and does not impose a structural or technical limitation that would distinguish over the combined teachings, but instead represents a conventional downstream medical action following diagnosis.
Accordingly, the rejection under 35 USC 103 is maintained.
New Rejections
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 16, 23-25, 27-28 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.
Claim 16 is rejected. Claim 16 recites the limitation "the group" in step (a) at line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim 16 is further rejected. Claim 16 recites the limitation "the presence" in step (c) at line 1. There is insufficient antecedent basis for this limitation in the claim.
Claims 23-25, 27-28 are included in this rejection due to their dependency on claim 16.
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 44-52 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
The claims recite method for diagnosing Alzheimer’s-related dementia by measuring biomarkers (Aβ peptides, tau proteins) in patient samples and conducting PET scans. Specifically, the correlation between levels of these naturally occurring biomarkers and the presence/progression of Alzheimer’s disease represents a natural law/phenomenon that exists in nature apart from any human action.
This judicial exception is not integrated into a practical application because the claims merely recite steps of measuring biomarker levels using conventional techniques (multiplexed assay kits) and performing standard PET scans using known radioactive agents (i.e., Pittsburgh Compound B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because measuring autoantibodies to Alzheimer’s-associated proteins and conducting PET scans represent well-understood, routine and conventional activities previously known in the industry. Specifically, when considered separately and in combination, the additional elements of measuring biomarkers using assay kits and conducting PET scans using known agents do not add significantly more to the exception itself and are not markedly different from observing the natural correlation between these biomarkers and Alzheimer’s disease.
Subject Matter Eligibility Test for Products and Processes
Step 1 - Is the Claim to a Process, Machine, Manufacture or Composition of Matter? YES.
The claims provide for methods of diagnosing Alzheimer’s-related dementia (claims 16, 21-25, 27-43). The methods involve measuring biomarker levels in patient samples and conducting PET scans to diagnose Alzheimer’s disease; citing a series of steps.
Thus, the claims are directed to a statutory category (e.g., process).
Step 2A, Prong One — Does the Claim Recite a Product of Nature? YES.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because, whether isolated or not, such naturally-occurring biomarkers (Aβ peptides and tau portions) and the presence/progression of Alzheimer’s disease, are deemed to fall under the judicial exception of natural products, and as such, are not patent-eligible subject matter pursuant to the Supreme Court decision in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 US 66 (2012).
In Mayo, the Court held that “if a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself.” Specifically, the Court held that relationships between concentrations of certain metabolites in the blood and the likelihood that a drug dosage will be ineffective or cause harm are not patent eligible. The correlation between the presence or levels of these biomarkers and Alzheimer’s diseases exists in principle apart from any human action, similar to the correlation at issue in Mayo.
Step 2A, Prong Two — Does the Claim Recite an Additional Elements that Integrate the Judicial Exception into a Practical Application? NO.
The Supreme Court has long distinguished between principles themselves, which are not patent eligible, and the integration of those principles into practical applications, which are patent eligible. However, absent are any additional elements recited in the claim beyond the judicial exceptions which integrate the exception into a practical application of the exception. The “integration into a practical application” requires an additional element or a combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that it is more than a drafting effort designed to monopolize the exception. The claim limitations “measuring, with a multiplexed assay kit comprising an array of antibodies configured to measure the level of each biomarker or panel,” “conducting a PET scan,” and “diagnosing from said measuring step” are not indicative of integration into a practical application. The above claim limitations are considered simply as the recitation of a naturally-occurring product. Thus, the claims do not provide for any element/step that integrates the law of nature into a practical application.
Step 2B - Does the Claim Recite Additional Elements that Amount to Significantly More than the Judicial Exception? NO.
The Supreme Court has identified a number of considerations for determining whether a claim with additional elements amounts to “significantly more” than the judicial exception(s) itself. The claims as a whole are analyzed to determine whether any additional element/step, or combination of additional elements/steps, in addition to the identified judicial exception(s) is sufficient to ensure that the claim amounts to “significantly more” than the exception(s).
However, the additional elements of the instant application, individually and in combination, do not amount to “significantly more” or “markedly different.” Under the Step 2B analysis, the “physical” elements of the claims are considered to be the same as those found in nature. For example, Andreasen et al. (“CSF markers for Alzheimer's disease: Total tau, phospho-tau and Aβ42”, The World Journal of Biological Psychiatry, published 7/12/2009, from IDS 10/5/2021) discloses that Tau is a normal brain phosphoprotein, which binds to microtubules in the neuronal axon, thereby promoting assembly and stability and exists in six different isoforms in the human brain (Figure 2; p. 148, Paragraph 2). Further, Andreasen discloses that the most commonly used ELISA, INNOTEST™ TAU Ag, for measurement of T-tau in CSF uses monoclonal anti-bodies that detect all isoforms of tau independent of phosphorylation state (Figure 2; p.148, Paragraphs 3-4). High T-tau and low Aβ42 in early Alzheimer’s Disease (AD), but with dementia have been found in several studies suggesting that these markers are positive early in the disease process and the addition of P-tau increases the specificity, since normal P-tau levels are found in most cases with frontotemporal and Lewy body dementia, and also in cerebrovascular disease showcasing that the combination of several of these markers (T-tau, Ab42 and P-tau) will increase the specificity for the diagnosis of AD (Table 4; p. 151, Paragraphs 1-5), thus establishing the natural tendencies used for detection of AD in clinical patients.
Further Du et al. (“Reduced levels of amyloid β-peptide antibody in Alzheimer disease”, Neurology, published 9/11/2001, from IDS 10/5/2021) discloses that senile (neuritic) plaques and neurofibrillary tangles comprise the major neuropathologic features of Alzheimer’s Disease (AD) and are spherical, multicellular lesions that are usually found in moderate to large numbers in limbic structures and association neocortex of AD brain, further comprised of extracellular deposits of amyloid-β peptide(s) (Aβ) that include abundant amyloid fibrils intermixed with nonfibrillar forms of the peptide (Introduction: Paragraph 1). Further, Du discloses that using an ELISA capture assay, anti-Aβ antibody in samples from control subjects who did not have dementia were detected (Figure 1) and further characterized via the specificity of this antibody, using ELISA with protein A agarose (Results: Paragraph 1). Du also discloses that because many of the AD samples investigated in this study have anti-Aβ antibody levels similar to those found in control samples, the role of these antibodies seems unlikely to be primary or at the core of the disease process (Discussion: Paragraphs 1-2) establishing the natural tendencies of Aβ antibodies in AD studies.
Additionally, Herholz et al. (“Clinical amyloid imaging in Alzheimer's disease”, The Lancet Neurology, published 7/2011, from IDS 10/5/2021) discloses a hypothesis that amyloid deposition is the leading cause of Alzheimer's disease (AD) is supported by findings in transgenic animal models and forms the basis of clinical trials of anti-amyloid agents showcasing that amyloid deposition causes severe damage to neurons many years before onset of dementia via a cascade of several downstream effects (Background: Paragraph 1). Further, Herholz discloses that most amyloid imaging in human beings is currently done in research studies with the 11C-labelled PET (Positron emission tomography) tracer PiB (Pittsburgh Compound B); however, the very short physical half-life (20 mins) of 11C requires that a cyclotron be available on-site for production of the isotope, which prevents widespread clinical use since PiB binds to insoluble fibrillary amyloid β with high affinity, but not to amorphous amyloid plaques and neurofibrillary tangles (Pittsburgh Compound B: Paragraph 1). Herholz also discloses that in place of PiB, all three 18F-labelled amyloid ligands undergoing clinical trials could be used to detect fibrillary amyloid in patients with AD with high sensitivity (Conclusions and Future Directions: Paragraph 1), showcasing the widespread use of PiB as a radioactive compound for usage in PET scans as diagnostic agents for AD patients.
Therefore, the claimed methods for diagnosing Alzheimer’s-related dementia are not deemed to be markedly different than the correlation between biomarkers and disease state found in nature. Simply noting that the method uses a multiplexed assay kit or conducts a PET scan with radioactive diagnostic agents is not sufficient to distinguish the claimed diagnostic methods from the natural correlation between biomarker levels and Alzheimer’s disease.
Thus, when viewed both individually and as an ordered combination, the claimed elements, in addition to the identified judicial exception are found insufficient to supply an inventive concept because the elements are not deemed to be markedly different from those found in nature. Accordingly, the claims do not qualify as patent-eligible subject matter.
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.
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 44-52 are rejected under 35 U.S.C. 103 as being unpatentable over Devanarayan et al. (WO 2011005893 A2; published 1/13/2011) in view of Herholz et al. (“Clinical amyloid imaging in Alzheimer's disease”, The Lancet Neurology, published 7/2011, from IDS 10/5/2021), and in further view of Greenfield et al. (US PGPub 2002/0054870; published 5/9/2002), and Birkett (US PGPub 2003/0138769 A1; published 7/24/2003), and Barghorn et al. (US PGPub 2011/0092445 A1; published 4/21/2011), and Watanabe et al. (US PGPub 2006/0241038 A1; published 10/26/2006), and Bridon et al. (US PGPub 2005/0187159 A1; published 8/25/2005), and Matsuda et al. (US PGPub 2010/0291122 A1; published 11/18/2010), and Chain (US PGPub 2006/0088548 A1; published 4/27/2006), and Krafft et al. (US PGPub 2007/0213512 A1; published 9/13/2007), and Audia et al. (US PGPub 2001/0020097 A1; published 9/6/2001).
Regarding claims 44-52, Devanarayan teaches methods for classifying a test sample as indicative of Alzheimer's disease use protein and peptide biomarkers that are differentially expressed in the cerebral spinal fluid (CSF) of subjects with Alzheimer's disease (AD) relative to age-matched controls including protein and peptide signatures indicative of Alzheimer's disease (Abstract). Devanarayan also teaches a kit for classifying a test sample obtained from a human subject, comprising reagents for detecting at least one protein or peptide biomarkers for detecting any one of the protein or peptide biomarker combinations (Tables 2A-4C; p. 4, Paragraph 2). Specifically, Devanarayan teaches that increases in total and p-tau and a concomitant decrease in Aβ l-42 in CSF may be indicative of AD; however, are not specific indicators (p. 1, Paragraph 2). Devanarayan further teaches that these proteins and peptides thus serve as biomarkers for classifying test samples, diagnostics or therapeutic monitoring, either individually or in a panel of biomarkers (p. 11, Paragraph 1).
Devanarayan also teaches another example of indirect labeling, polypeptides capable of specifically binding immunoglobulin constant regions, such as polypeptide A or polypeptide G, can also be used as labels for detection antibodies, which are normal constituents of the cell walls of streptococcal bacteria and can thus be labeled and added to the assay mixture, where they will bind to each capture and detection antibody, as well as to the autoantibodies, labeling all and providing a composite signal attributable to analyte and autoantibody present in the sample (p. 22, Paragraphs 2-3). Specifically, Devanarayan teaches that each primer or probe within the array or kit is capable of specifically hybridizing under stringent conditions to a protein or peptide biomarker (i.e., tau, Aβ peptides) where the different primers or probes may consist of a minimum number of different primers or probes needed to specifically hybridize under stringent conditions to each protein or peptide biomarker (i.e., first or second) and directly correlated with detecting the presence of disease at its earliest stage (Tables 2A, 2B, 3B, 3C, 4B, 4C and 5; p. 24, Paragraph 2).
Further, Devanarayan teaches a method for classifying Alzheimer's disease (AD) state of a subject, comprising: a) selecting a statistically relevant multi-analyte panel from fluid samples obtained from human subjects including a control cohort consisting of healthy subjects and an AD cohort consisting of subjects diagnosed with AD, in which panel a plurality of protein or peptide biomarkers are differentially expressed to provide expression values for a reference AD panel and a control panel; b) conducting a Random Forests or Simulated Annealing analysis on the multi-analyte data from step (a) to derive a signature; c) applying a classification algorithm to the signature of step (b) to refine the signature; d) obtaining a test fluid sample from the subject; e) determining expression level in the test sample for each of the protein biomarkers used to specify the panel of (a); f) providing the results of step (e) to the classification model on the signature obtained from step (c) to obtain an output; and g) determining the classification of the disease state according to the output of step f), wherein the classification is either AD or control (p. 2-3; Paragraph 1). Specifically, Devanarayan teaches that increases in total and p-tau and a concomitant decrease in Aβ l-42 in CSF may be indicative of AD; however, are not specific indicators (p. 1, Paragraph 2).
Devanarayan does not teach or suggest specific sequences disclosed in Aβ 42, 40, 38, 39, 37, 34, 43, 16, 17 or combinations of A-beta peptides as biomarkers. Devanarayan does not teach or suggest the use of a PET scan of a patient’s brain to estimate plaque density in a patient via radioactive diagnostic agent for treatment of physical symptoms.
Herholz teaches a hypothesis that amyloid deposition is the leading cause of Alzheimer's disease (AD) is supported by findings in transgenic animal models and forms the basis of clinical trials of anti-amyloid agents showcasing that amyloid deposition causes severe damage to neurons many years before onset of dementia via a cascade of several downstream effects (Background: Paragraph 1). Further, Herholz teaches that most amyloid imaging in human beings is currently done in research studies with the 11C-labelled PET (Positron emission tomography) tracer PiB (Pittsburgh Compound B); however, the very short physical half-life (20 mins) of 11C requires that a cyclotron be available on-site for production of the isotope, which prevents widespread clinical use since PiB binds to insoluble fibrillary amyloid β with high affinity, but not to amorphous amyloid plaques and neurofibrillary tangles (Pittsburgh Compound B: Paragraph 1). Further, Herholz teaches that among possible markers of early Alzheimer's disease (AD), the Pittsburgh compound B (PiB) seems to be a sensitive and specific marker of amyloid-β deposition (Herholz: Introduction, Paragraph 1). Herholz also teaches that in place of PiB, all three 18F-labelled amyloid ligands undergoing clinical trials could be used to detect fibrillary amyloid in patients with AD with high sensitivity (Conclusions and Future Directions: Paragraph 1). Herholz also teaches that although early clinical phenotypes, such as mild cognitive impairment (MCI), have been explored, only some patients actually progress to dementia; therefore, additional markers of prognosis and underlying pathology are needed to identify patients early in the disease course (Introduction: Paragraph 1).
PNG
media_image1.png
142
648
media_image1.png
Greyscale
[AltContent: textbox (Figure 1: Greenfield’s SEQ ID NO. 2 is a 100% match to Aβ16 of the instant application. )]Greenfield teaches specified peptide synergism with amyloids and their contribution to Parkinson’s and Alzheimer’s diseases via the calcium channel (Abstract). Further, Greenfield’s artificial peptide sequence, SEQ ID NO. 2 (p. 6), is the same sequence as Aβ16 of the instant application, as shown in Figure 1, below.
Birkett teaches stability of self-assembled particles is obtained by the presence of at least one heterologous cysteine residue near the carboxy-terminus of the chimer molecule in relation to the hepatis B virus nucleocapsid protein (Abstract). Further, Birkett’s peptide sequence, SEQ ID NO. 188 (p. 81), is the same sequence as Aβ17 of the instant application, as shown in Figure
PNG
media_image3.png
122
637
media_image3.png
Greyscale
2, below.
[AltContent: textbox (Figure 2: Birkett’s SEQ ID NO. 188 is a 100% match to Aβ17 of the instant application. )]
Barghorn teaches specified amyloid β peptide analogues (Abstract). Further, Barghorn’s artificial peptide sequence, SEQ ID NO. 208 (p. 16), is the same sequence as Aβ34 of the instant application, as shown in Figure 3, below.
PNG
media_image4.png
125
679
media_image4.png
Greyscale
[AltContent: textbox (Figure 3: Barghorn’s SEQ ID NO. 208 is a 100% match to Aβ34 of the instant application. )]
[AltContent: textbox (Figure 4: Watanabe’s SEQ ID NO. 12 is a 100% match to Aβ37 of the instant application. )]
PNG
media_image6.png
135
633
media_image6.png
Greyscale
Watanabe teaches specified amyloid β peptide pharmaceutical compositions, specifically Aβ37 (Abstract). Further, Watanabe’s human enzyme sequence, SEQ ID NO. 12 (p. 16), is the same sequence as Aβ37 of the instant application, as shown in Figure 4, below.
PNG
media_image7.png
133
633
media_image7.png
Greyscale
[AltContent: textbox (Figure 5: Bridon’s SEQ ID NO. 1002 is a 100% match to Aβ38 of the instant application. )]Bridon teaches a method for protecting a peptide from peptidase activity in vivo, the peptide being composed of between 2 and 50 amino acids and having a C-terminus and an N-terminus and a C-terminus amino acid and an N-terminus amino acid (Abstract). Further, Bridon’s synthetic peptide sequence, SEQ ID NO. 1002 (p. 13), is the same sequence as Aβ38 of the instant application, as shown in Figure 5, below.
PNG
media_image9.png
133
633
media_image9.png
Greyscale
Matsuda teaches a method for enhancing an immune response and a medicament for preventing or treating Alzheimer disease comprising amyloid β peptide that induces an enhanced immune response (Abstract). Further, Matsuda’s synthetic peptide sequence, SEQ ID NO. 29 (p. 3), is the same sequence as Aβ39 of the instant application, as shown in Figure 6, below.
[AltContent: textbox (Figure 6: Matsuda’s SEQ ID NO. 29 is a 100% match to Aβ39 of the instant application. )]
Chain teaches a chimeric peptide or mixture of chimeric peptides that can be formulated as an immunizing composition and used in a method for immunization of a mammal against an internal peptide (Abstract). Further, Chain’s human enzyme sequence, SEQ ID NO. 2 (p. 11), is the same sequence as Aβ40 of the instant application, as shown in Figure 7, below.
PNG
media_image10.png
155
635
media_image10.png
Greyscale
[AltContent: textbox (Figure 7: Chain’s SEQ ID NO. 2 is a 100% match to Aβ40 of the instant application. )]
Krafft teaches specified amyloid β peptides for the assembly of vaccines (Abstract). Further, Krafft’s artificial polypeptide sequence, SEQ ID NO. 5 (p. 5), is the same sequence as Aβ42 of the instant application, as shown in Figure 8, below.
PNG
media_image12.png
129
684
media_image12.png
Greyscale
[AltContent: textbox (Figure 8: Krafft’s SEQ ID NO. 5 is a 100% match to Aβ42 of the instant application. )]
Audia compounds which inhibit β-amyloid peptide release and/or its synthesis, which
PNG
media_image14.png
141
635
media_image14.png
Greyscale
[AltContent: textbox (Figure 9: Audia’s SEQ ID NO. 1 is a 100% match to Aβ43 of the instant application. )]and, accordingly, have utility in treating Alzheimer's disease (Abstract). Further, Audia’s precursor protein SEQ ID NO. 1 (p. 7), is the same sequence as Aβ43 of the instant application, as shown in Figure 9, below.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Devanarayan’s biomarker panel approach with Herholz’s PET-scanning technique to create a more comprehensive diagnostic method for Alzheimer’s disease. This combination would provide complementary diagnostic information: biomarker measurements indicating molecular changes associated with AD and PET imaging directly visualizing amyloid plaque deposits in the brain. Further, the specific biomarkers claimed (Aβ16, 17, 43, 34, 37, 39, 38, 40 42 and total-tau, P-tau and C-tau) would have been obvious to include based on the teachings of Greenfield, Barghorn, Watanabe, Bridon, Matsuda, Birkett, Chain, Audia and Krafft, which collectively suggest the diagnostic value of these specific biomarkers. Further, the motivation to combine these references is further supported by the recognized need in the art for more accurate early diagnosis of AD. For example, Devanarayan teaches that biomarkers can be used for early detection of AD and Herholz further emphasize that amyloid decomposition occurs many years before onset of dementia, suggesting the value of combining different diagnostic approaches for earlier and more accurate detection.
A person of ordinary skill in the art would have had a reasonable expectation of success in combining these prior art elements due to both biomarker measurement techniques and PET scanning being well-established in relation to tracing and scanning for β-amyloids. Further, a correlation between the two technique was well-established at the time of the invention, since Herholz teaches that PET imagining can reliably detect amyloid plaques and Devanarayan teaches that changes in tau and Aβ levels are indicative of AD for diagnostic purposes.
Specifically, both techniques, as well as the teachings of Greenfield, Barghorn, Watanabe, Bridon, Matsuda, Birkett, Chain, Audia and Krafft for the specified sequences, provide specific technical details that would enable one skilled in the art to implement the combined method. For example, Greenfield provides the exact sequence of Aβ16, within the same context of amyloids and their contribution to Parkinson’s and Alzheimer’s diseases, as both Herholz and Devanarayan. Therefore, the combination of Devanarayan’s biomarker approach with Herholz’s imaging technique, along with the specific biomarkers taught by additional references, would have been obvious through routine optimization and testing of known Alzheimer’s related peptides.
Conclusions
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELIZABETH ROSE LAFAVE whose telephone number is (703)756-4747. The examiner can normally be reached Compressed Bi-Week: M-F 7:30-4:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached on 571-272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ELIZABETH ROSE LAFAVE/ Examiner, Art Unit 1684
/HEATHER CALAMITA/ Supervisory Patent Examiner, Art Unit 1684