DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on October 10, 2025 has been entered. Any rejections or objections not reiterated herein have been withdrawn.
Applicants election of the combination of IL-6, IL-10, CRP, TNFα, FABP, and PPY is reiterated for the record.
Claims 10-18 are currently pending.
Claims 10-18 have been examined to the extent that the claims read on the elected biomarkers (IL-6, IL-10, CRP, TNFα, FABP, and PPY). The additionally recited biomarkers and combinations thereof have been withdrawn from consideration as being directed to non-elected subject matter. Prior to allowance of the claim, any non-elected subject matter that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Claim Rejections - 35 USC § 112(a)
3. The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 10-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method of identifying a human subject having Alzheimer’s disease (AD) that is likely to respond to treatment with rosiglitazone, the method comprising:
obtaining a blood, plasma, or serum sample from the human subject having AD;
measuring in the sample the expression levels of six proteins, wherein the six proteins are TNFα, IL-6, CRP, IL-10, FABP, and PPY;
determining that the expression levels of the six proteins in the sample are statistically similar to the expression levels of the six proteins in reference samples obtained from a population of AD patients that responded to treatment with rosiglitazone;
identifying the human subject having AD as being likely to respond to treatment with rosiglitazone based on the determining step; and
administering rosiglitazone to the human subject having AD.
does not reasonably provide enablement for the claims as broadly written. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Scope of the Claims/Nature of the Invention
The claims are drawn to a method of treating a human Alzheimer’s disease (AD) patient to improve cognition or prevent cognitive decline or dysfunction.
The claims recite a first step of obtaining a blood, plasma, or serum sample from the patient.
The claims recite a second step of measuring in the sample the expression level of TNFα, IL-6, CRP, IL-10, FABP, and PPY. The claims broadly encompass measuring mRNA levels or protein levels.
The claims recite a third step of determining that the patient has both a proinflammatory endophenotype profile and a metabolic endophenotype profile based on a comparison of the expression level of TNFα, IL-6, CRP, IL-10, FABP, and PPY to a reference expression level of TNFα, IL-6, CRP, IL-10, FABP, and PPY from a reference patient. The claims state that the comparison indicates that the patient has both the proinflammatory endophenotype and the metabolic phenotype when: (i) the reference patient is representative of an individual without Alzheimer's disease and the expression level of at least one of TNFα, IL-6, CRP, IL-10, FABP, and PPY is elevated as compared to the reference expression level of TNFα, IL-6, CRP, IL-10, FABP, and PPY; or (ii) the reference patient is representative of an individual having Alzheimer's disease with the proinflammatory endophenotype and the metabolic endophenotype and the expression level of at least one of TNFα, IL-6, CRP, IL-10, FABP, and PPY is statistically similar as compared to the reference expression level of TNFα, IL-6, CRP, IL-10, FABP, and PPY. The claims require measuring a combination of 6 genes, yet only ONE of those six genes has to be elevated or statistically similar with respect to the reference, for the patient to be determined as having the proinflammatory endophenotype profile and metabolic endophenotype profile.
The claims recite a fourth step of administering a PPAR-γ agonist to the patient. Claim 14 states that the PPAR-γ agonist is rosiglitazone or rosiglitazone XR.
The nature of the invention requires a reliable correlation between the expression level of TNFα, IL-6, CRP, IL-10, FABP, and PPY and a proinflammatory endophenotype profile and a metabolic endophenotype.
Teachings in the Specification and Examples
The specification (Example 7) pertains to a precision medicine approach to treating Alzheimer's disease using rosiglitazone therapy.
The specification (para 0256) teaches that peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists are widely used for treatment of diabetes. PPAR-γ agonists such as rosiglitazone modulate many cellular processes, including several associated with AD through its reduction of tau and amyloid pathology and inhibition of inflammation. The specification teaches that rosiglitazone was examined as a potential treatment for mild-to-moderate AD in the REFLECT trials but these clinical trials did not meet clinical endpoints. However, it was hypothesized that the one-size-fits-all approach to the clinical trial design masked the therapeutic benefit experienced by a subset of patients. Methods were tested to create a predictive biomarker that identifies those specific AD patients that benefited from rosiglitazone therapy in the REFLECT trials.
The specification (para 0258-0259) teaches that the current study included samples and data from multiple trials of rosiglitazone therapy for mild-to-moderate AD. Participants in the trials were 50-90 years old with a diagnosis of mild-to-moderate AD according to NINDS-ADRDA criteria, Mini Mental Status Examination (MMSE) score between 10-26 at screening and at least 6-months of ongoing donepezil or other approved AChEI therapy with stable dosing for at least 2 months prior to enrollment.
The specification (0261-0263) teaches that proteomic assays were performed to detect biomarkers in blood. Plasma samples were assayed via multi-plex biomarker assay platform using electrochemiluminescence (ECL). All plasma samples were assayed for targeted markers of our proinflammatory endophenotype and metabolic endophenotype: c-reactive protein (CRP), interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNF-α), fatty acid binding protein (FABP)-3, and pancreatic polypeptide (PPY).
The specification (para 0264) teaches that a predictive biomarker profile was generated using support vector machine (SVM) analyses. The specification teaches that building of the predictive biomarker was based on responders versus non-responders (i.e. only 2 groups). Treatment responder was defined as an MMSE score that was stable or improved over trial duration whereas non-responder was defined as any decline in MMSE scores over the clinical trial duration. The goal of responder was to identify those who experience clinically meaningful outcomes rather than slowed decline. The purpose of this approach was to have a predictive biomarker that could selectively identify only those most likely to respond while all others would be ruled out.
The specification (paras 0266-0270) teaches that a total of 534 samples were assayed as part of this proof-of-concept study. First, the predictive biomarker was examined using pre-specified inflammatory and metabolic markers, which included IL-6, IL-10, CRP, TNFα, FABP-3, and PPY. These markers were used to predict treatment response versus non-response (based on change in MMSE score) within each clinical trial. In the Phase 2 trial (AVA100193), there was a total of 31 responders and 19 non-responders in the 2 mg arm, 28 responders and 24 non-responders in the 4 mg arm and 26 responders and 17 non-responders in the 8 mg arm. Using the 6-protein algorithm, 100% of patients were correctly classified across study arms (FIG. 22). In the Phase 3 trial (AVA105640), there was 20 responders and 25 non-responders in the 2 mg XR group and 22 responders and 23 non-responders in the 8 mg XR group. Using the 6-protein predictive biomarker algorithm, 100% of the patients were correctly classified as responder or non-responder (FIG. 23). In the Phase 3 trial (AV102672), there was 7 responders and 17 non-responders in the 2 mg XR arm and 12 responders and 17 non-responders in the 8 mg XR arm. The 6-protein predictive biomarker algorithm was 100% accurate in identifying responders versus non-responders (FIG. 24). In the Phase 3 trial (AVA102670), there were 7 responders and 23 non-responders in the 2 mg XR arm and 20 responders and 22 non-responders in the 8 mg XR arm. The 6-protein predictive biomarker algorithm was 100% accurate in identifying responder versus non-responder (FIG. 25).
The specification (paras 0271-0272) teaches that the data was combined across the 2 mg XR and 8 mg XR arms across trials. There were 34 responders and 65 non-responders in the 2 mg XR arm and 54 responders and 62 non-responders in the 8 mg XR arm. When the data was combined across these arms, the 6-protein predictive biomarker algorithm was again 100% accurate in identifying responders versus non-responders to rosiglitazone (FIG. 26). Additionally, data was combined across all rosiglitazone therapy arms to determine if a global RSG-predictive biomarker could be generated. When combined across arms and trials, there were 173 responders and 187 non-responders. The 6-protein predictive biomarker was 98% accurate overall with 98% of treatment responders accurately classified (FIG. 27).
State of the Art and the Unpredictability of the Art
While methods of measuring expression level of biomarkers are known in the art, methods of correlating those biomarkers with a phenotype (such as a high proinflammatory endophenotype and a metabolic endophenotype) are highly unpredictable. The unpredictability will be discussed below.
The claims recite a step of determining that the patient has both a proinflammatory endophenotype profile and a metabolic endophenotype profile based on the expression level of IL-6, IL-10, CRP, TNFα, FABP and PPY (see clm 10). First of all it is relevant to note that the specification does NOT teach a correlation between the expression level of these biomarkers and a proinflammatory endophenotype profile and a metabolic endophenotype. Rather the examples in the specification teach a correlation between these biomarkers and response to treatment with rosiglitazone in patients with AD. The specification teaches that the 6-protein predictive biomarker algorithm was highly accurate in identifying responders versus non-responders.
The claims recite a step of determining that the patient has both a proinflammatory endophenotype profile and a metabolic endophenotype profile when the expression level of ONE of IL-6, IL-10, CRP, TNFα, FABP and PPY is elevated or similar to the reference. However it is highly unpredictable if one could determine that a patient has both a proinflammatory endophenotype profile and a metabolic endophenotype profile based on a SINGLE gene. The specification does not provide support for this, as the specification teaches a 6-protein predictive biomarker algorithm. Only claim 13 requires that EACH of IL-6, IL-10, CRP, TNFα, FABP and PPY are elevated or similar to the reference expression values.
The claims encompass embodiments wherein the patient is determined to have both the proinflammatory endophenotype and the metabolic endophenotype when the reference patient is representative of an individual without AD and the expression level of at least one of IL-6, IL-10, CRP, TNFα, FABP and PPY is elevated as compare to the reference expression level of the one or more corresponding biomarkers. This statement, which is not supported by any evidence in the specification is highly unpredictable. It is noted that there is NO data in the specification on the expression levels of IL-6, IL-10, CRP, TNFα, FABP and PPY in blood, plasma, or serum samples obtained from patients without AD. The teachings in the specification pertain to the analysis of the expression of theses biomarkers in AD patients that responded to rosiglitazone (stable or improved) compared to AD patients that did not respond to rosiglitazone (declined). In the absence of evidence to the contrary it is highly unpredictable what the levels of these biomarkers will be in patients without AD.
Because the claims encompass biomarkers which can be either nucleic acids or proteins, it is relevant to mention that it is highly unpredictable as to whether or not a measure of nucleic acid expression is indicative of the level of protein in a sample or vice versa. The post-filing art of Chan (G&P magazine 2006 Vol 6 No 3 pages 20-26). teaches that cells have elaborate regulatory mechanisms at the level of transcription, post-transcription, and post-translation (p.1, last paragraph), and that transcript and protein abundance measurements may not be concordant (p.3, sixth full paragraph). Thus it is unpredictable as to whether or not the results pertaining to protein expression, as presented in the instant specification, would be applicable to methods requiring or encompassing the analysis of nucleic acid samples.
Quantity of Experimentation:
It is noted that the claimed methods encompass being able determine that a Alzheimer’s Disease patient has a proinflammatory endophenotype profile and a metabolic endophenotype profile based on the expression level of at one of IL-6, IL-10, CRP, TNFα, FABP and PPY.
In order to practice the full scope of the invention, one would have to obtain a large number of Alzheimer’s disease patients with proinflammatory endophenotype profile and a metabolic endophenotype profile and a large number of Alzheimer’s disease patients without the proinflammatory endophenotype profile and a metabolic endophenotype profile. Then one of skill in the art would have to measure the mRNA and protein level of each of IL-6, IL-10, CRP, TNFα, FABP and PPY in a blood, plasma, or serum sample obtained from the patients. Then all the data would have to be analyzed to determine which single biomarker and which combinations of biomarkers can separate AD patients having the proinflammatory endophenotype profile and a metabolic endophenotype profile from AD patients without the
proinflammatory endophenotype profile and a metabolic endophenotype profile. Once the patients are identified then they would need to be treated with PPARγ agonists and monitored overtime to see if they respond to the treatment. The results of such experimentation are highly unpredictable.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue. Attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even “a considerable amount of experimentation is permissible,” as long as it is “merely routine” or the specification “provides a reasonable amount of guidance” regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360-61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is “not without bounds.” Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation “would be excessive, e.g., that it would involve testing for an unreasonable length of time.” 707 F.3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a “diverse and relatively poorly understood group of microorganisms,” with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Additionally, attention is directed to Cephalon at 1823, citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 218 USPQ 961, that work that would require 18 months to 2 years so to enable the full scope of an invention, even if routine, would constitute undue experimentation. As stated therein:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years’ work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] Fed. Cir.1983). (Emphasis added)
Attention is also directed to MPEP 2164.06(b) and In re Vaeck, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Where, as here, a claimed genus represents a diverse and relatively poorly understood group of microorganisms, the required level of disclosure will be greater than, for example, the disclosure of an invention involving a “predictable” factor such as a mechanical or electrical element. See Fisher, 427 F.2d at 839, 166 USPQ at 24.
In view of such legal precedence, the aspect of having to work for so many years just to provide the starting materials for minute fraction of the scope of the claimed invention is deemed to constitute both an unreasonable length of time and undue experimentation.
Conclusions:
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Response To Arguments
4. In the response the Applicants traversed the rejection under 35 USC 112(a). The Applicants note that claim 10 has been amended to recite that an elevated expression level of the one or more biomarkers as compared to a reference patient without Alzheimer's disease, OR a statistically similar expression level of the one or more biomarkers as compared to a reference patient having Alzheimer's disease with the proinflammatory endophenotype and the metabolic endophenotype IS indicative of the patient having the proinflammatory endophenotype and the metabolic endophenotype. Applicant submits that in view of this amendment the current rejection moot.
The claims amendments have been fully considered but do not overcome the rejection. The rejection is maintained for several reasons. The claims recite a correlation between the expression level of IL-6, IL-10, CRP, TNFα, FABP and PPY and a patient having both a proinflammatory endophenotype profile and a metabolic endophenotype profile. This is not commensurate with the teachings in the specification which discloses a correlation between these biomarkers and response to treatment with rosiglitazone in patients with AD. Secondly Claim 10 as amended requires only that a SINGLE biomarker (opposed to each of the 6 biomarkers) be elevated or have similar to the expression level of the corresponding biomarker for the patient to be identified as having the claimed endophenotype. The specification teaches that the 6-protein predictive biomarker algorithm was highly accurate in identifying responders versus non-responders. There is no evidence in the specification that a SINGLE biomarker or different combinations of 2-5 of these biomarkers would be accurate in identifying responders versus non-responders. The claims encompass comparisons to reference patients without AD. It is noted that there is NO data in the specification on the expression levels of IL-6, IL-10, CRP, TNFα, FABP and PPY in blood, plasma, or serum samples obtained from patients without AD. In the absence of evidence to the contrary it is highly unpredictable what the levels of these biomarkers will be in patients without AD. Finally the claims encompass the analysis of mRNA and protein, yet the teachings in the specification pertain to protein. The prior art teaches that it is highly unpredictable if mRNA and protein levels are concordant. For these reasons the rejection is maintained.
It is noted for the record that amending the claims to recite the enabled subject matter indicated on page 3 would overcome this rejection.
Improper Markush Grouping Rejection
5. Claims 10-18 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The claims recite the following Markush groups:
measuring in the sample the expression level of one or more biomarkers selected from the group consisting of interleukin (IL)-7, tumor necrosis factor-alpha (TNFa), IL-5, IL-6, C- reactive protein (CRP), IL-10, tenascin C (TNC), intracellular adhesion molecule-1 (ICAM1), coagulation factor VII (Factor VII), 1309, tumor necrosis factor receptor-1 (TNFR1), alpha-2 macroglobulin (A2M), chemokine (C-C motif) ligand 17 (TARC), eotaxin3, vascular cell adhesion molecule-1 (VCAM1), thrombopoietin (TPO), fatty acid binding protein (FABP), IL- 18, beta-2 microblogulin (B2M), serum amyloid Al cluster (SAA), pancreatic polypeptide(PPY), Parkinson protein 7 (DJ1), beta amyloid (Ap), tau, a-synuclein, glucagon like peptide 1 (GLP-1), peptide YY (PYY), insulin, glycated hemoglobin Alc (HbAlc), high density lipoprotein (HDL), low density lipoproteins (LDL and vLDLs), diacylglycerol acyl- transferase 1 (DGAT1), peroxisome proliferator-activated receptor (PPAR)-y,and PPARa (clm 10)
one or more biomarkers selected from IL-6, IL-10, CRP, TNFa, FABP and PPY (clms 12, 16)
These Markush groupings are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
MPEP 2117(II) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)).
MPEP 2117(II) further state that alternatives (1) share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class and (2) share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent in the context of the claimed invention.
MPEP § 2117(II)(A) states that “A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”. Herein the members of the Markush grouping are all gene/proteins. These do not belong to the same recognized physical or chemical class or to the same art-recognized class because there is no expectation from the art that each of the recited genes/proteins would function in the same way in the claimed method. It is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention. Further it is noted that the genes/proteins do not share a common use/function because the specification (pages 28-30) discusses the use of FABP and pancreatic polypeptide (PPY) in connection with the metabolic endophenotype and the specification (pages 62-68) discusses the measurement of IL-6, IL-10, CRP, and TNFa in connection with the proinflammatory endophenotype.
MPEP § 2117(II)(B) states that “Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as explained in subsection IIA above, the members of the Markush grouping may still be considered to be proper where the alternatives share a substantial structure feature that is essential to a common use. Again the members of the Markush grouping are all gene/proteins. While they are all made up of nucleic acids or amino acids, the structure of comprising nucleic acids or amino acids is not essential to any asserted common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response To Arguments-Improper Markush Rejection
6. In the response the Applicants traversed the Improper Markush group rejection. The Applicants note that a nearly identical issue was addressed in Ex Parte Malcolm Andrew Ward, Abdul Hve, Simon Harold Lovestone, & Riclard James Butler Dobson, No APPEAL 2021-003776, 2022 WL 2129258 (P T.A.B June 10, 2022). The Applicants argue that although the decision is not precedential, there is nearly an identical fact pattern in the instant case.
This argument has been fully considered but is not persuasive. The cited Ex Parte Ward decision is a Board decision and thus not binding legal precedent. In general, precedential decision that must be followed if they are relevant to the issue under consideration will be from the Supreme Court, the Court of Appeals for the Federal Circuit, or the Court of Customs and Patent Appeals. The MPEP sometimes cites Board decisions. Generally, this occurs when there is no precedential court decision (Supreme Court, Federal Circuit, or Court of Customs and Patent Appeals) that addresses a particular issue, but the Office has adopted the Board’s reasoning about the issue as patent examination policy. The case cited by Applicants is a Board decision that is not cited in the MPEP. Therefore the examiner is not obligated to follow it. The Examiner maintains that Applicants have not met the burden of establishing that the recited polypeptides have a single structural similarity and a common use. While the genes/proteins are all made up of nucleic acids or amino acids, they do not share a common structure. Additionally the genes/proteins do not share a common use because the specification (pages 28-30) discusses the use of FABP and pancreatic polypeptide (PPY) in connection with the metabolic endophenotype and the specification (pages 62-68) discusses the measurement of IL-6, IL-10, CRP, and TNFa in connection with the proinflammatory endophenotype. These are two different uses. The rejection is maintained.
This rejection can be overcome be amending the claim 10 such that it only recites the elected combination of biomarkers. Applicants could then add a dependent claim that is directed to a method further comprising measuring the expression level of the non-elected biomarkers.
Double Patenting
7. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
8. Claims 10-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-18 of copending Application No. 18/548,840 (copending application). Although the claims at issue are not identical, they are not patentably distinct from each other.
In the instant case, both sets of claims are drawn to a method of treating a human Alzheimer's disease patient to improve cognition or to prevent cognitive decline or dysfunction in the patient (see clm 10 of the copending application). Both sets of claims require obtaining a blood, plasma, or serum sample from the patient; measuring in the sample the expression level of tumor necrosis factor-alpha (TNFa), IL-6, C- reactive protein (CRP), IL-10, fatty acid binding protein (FABP), pancreatic polypeptide (PPY);determining that the patient has both a proinflammatory endophenotype profile and a metabolic endophenotype profile based on a comparison of the expression level of the biomarkers to a reference expression level of the biomarkers from a reference patient; and administering a PPAR-y agonist to the patient (see clms 10-13 of the copending application). Further both sets of claims state that the patient has both the proinflammatory endophenotype and the metabolic phenotype when: the reference patient is representative of an individual having Alzheimer's disease and the expression level of at least one of TNFα, IL-6, CRP, IL-10, FABP, and PPY is statistically similar as compared to the reference expression level of TNFα, IL-6, CRP, IL-10, FABP, and PPY. The instant claims are different from the copending claims because they state that the reference patient with AD has the proinflammatory and metabolic endophenotype. It is noted that portions of the specification which provide support the copending claims may also be examined and considered when addressing the issues of whether a claim defines an obvious variation of an invention. Herein the specification of the ‘840 teaches comparison to reference patients with AD having the proinflammatory and metabolic endophenotype. It would have been obvious to have modified the method of the copending claims by comparing to reference patients with AD having the proinflammatory and metabolic endophenotype since the goal of the method is to identify additional AD patients with the proinflammatory and metabolic endophenotype. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response To Arguments-Double Patenting
9. In the response the Applicants traversed the double patenting rejection. The Applicants argue that the claims as amended recite that the patient has both the proinflammatory endophenotype and the metabolic endophenotype when: the reference patient is representative of an individual without Alzheimer's disease and the expression level of at least one of the one or more biomarkers is “elevated” as compared to the reference expression level of the one or more corresponding biomarkers. They argue that in contrast the claims of the '840 Application recite a “statistically different expression level”.
This argument has been considered but is not persuasive. The instant claims set forth two alternative ways in which the patient can be determined to have the proinflammatory endophenotype and the metabolic endophenotype. The first is based on a comparison to patients without AD and the second is based on a comparison to patients with AD. Since these are recited in the alternative, the ‘840 only needs to recite one of the alternatives for the ODP rejection to be proper. Herein both sets of claims recite that the patient has both the proinflammatory endophenotype and the metabolic phenotype when: the reference patient is representative of an individual having Alzheimer's disease and the expression level of at least one of TNFα, IL-6, CRP, IL-10, FABP, and PPY is statistically similar as compared to the reference expression level of TNFα, IL-6, CRP, IL-10, FABP, and PPY. The rejection is maintained.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682