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. This action is in response to the papers filed April 21, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Applicants election of the combination of IL-6, IL-10, CRP, TNFα, FABP, and PPY is reiterated for the record.
Claims 10-18 and 31 are currently pending.
Claim 31 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected subject matter (non-elected biomarkers).
Claim Rejections - 35 USC § 112(a)
3. 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 10-18 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.
Regarding Claims 10-18 it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites a method of identifying a human subject having AD that is likely to respond to treatment with a PPAR-γ agonist, yet the method only requires steps of “obtaining”, “measuring”, “determining” a endophenotype, and “administering” a PPAR-γ agonist. Thus it is not clear if applicant intends to cover only a method of “obtaining”, “measuring”, “determining” a endophenotype, and “administering” a PPAR-γ agonist OR if the method is intended to somehow require more to accomplish the goal set forth in the preamble (specifically the likelihood of responding to treatment). If it is the later, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal set forth by the preamble of the claims.
Claims 11-13 and 16 are rejected over the recitation of the phrase “reference subjects”. There is insufficient antecedent basis for this limitation in the claim because although claim 10 refers to a “reference subject”, it does not refer to “reference subjects”. The claims are confusing because it is unclear if they are intended to be limited to a single reference subject or if they encompass a plurality of reference subjects. Clarification is required.
Claim Rejections - 35 USC § 112
4. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 12 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. In the instant case claim 12 fails to further limit the subject matter of claim 11 because each of the limitations of claim 12 are already set forth in claim 11 (when read in combination with claim 10). Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
5. 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 identifying a human subject having AD that is likely to respond to treatment with a PPAR-γ.
The claims recite a first step of obtaining a blood, plasma, or serum sample from the human subject.
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 human subject 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 corresponding biomarkers from a reference subject. The claims state that the comparison indicates that the human subject has both the proinflammatory endophenotype and the metabolic phenotype when: (i) the reference subject is representative of an individual without Alzheimer's disease and the expression level of at least one of TNFα, IL-6, CRP, IL-10 AND at least one of FABP, and PPY is elevated as compared to the reference expression level of corresponding biomarkers; or (ii) the reference subject 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 AND at least one of FABP, and PPY is statistically similar as compared to the reference expression level of the corresponding markers. The claims require measuring a combination of 6 genes, yet only TWO 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. Additionally the claims require a reliable correlation between the expression level of TNFα, IL-6, CRP, IL-10, FABP, and PPY and the responsiveness to treatment with a PPAR-γ agonist.
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 AND one of 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 two genes. 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 least one of IL-6, IL-10, CRP, TNFα AND at least one of 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 combinations of two or more 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
6. In the response the Applicants traversed the rejection under 35 USC 112(a). In the response the Applicants argue that the specification (beginning on page 69) includes a section title "Method of diagnosing a subject as having a combination proinflammatory and metabolic endophenotype profile." They argue that this section states that the expression level of one or more of IL-6, IL-10, CRP, TNFa, FABP, and PPY is measured. In another embodiment, the expression level of one or more of IL-6, IL-10, CRP, TNFa and the expression level of one or more of FABP and PPY is measured. In another embodiment, the expression level of
each of IL-6, IL-10, CRP, TNFa, FABP, and PPY is measured. Therefore the argue that the Office Action is incorrect in asserting that the specification does not teach a correlation between the expression level of these biomarkers and a proinflammatory endophenotype profile and a metabolic endophenotype.
This argument has been fully considered but is not persuasive. While the specification makes assertions that these would work, there is no evidence that they actually do work. In other words these statements made in the specification are not commensurate in scope with the working examples that have been provided. There is no data in the specification that provides support for the claims as broadly written.
Further the Applicants argue that to practice the claimed invention, one skilled in the art only needs to obtain a sample from a human subject, compare the expression level of the recited biomarkers to corresponding expression levels from a reference subject, determine that the subject has both a proinflammatory endophenotype profile and metabolic endophenotype profile based upon the comparison, and administer a PPAR-y agonist to the human subject having the combination endophenotype. There is no requirement that a reference subject be independently/newly generated, that the measured biomarker levels be analyzed to determine which biomarker levels are representative of the combined endophenotype, or that patients identified as having the combination endophenotype be monitored over time to see if they respond to the PPAR-y agonist. In contrast, the application and the claims explicitly state how differing levels of the specific biomarkers relate to the determination of whether the subject has the combination endophenotype, and that individuals having the combined endophenotype are responsive to the PPAR-y agonist.
This argument has been fully considered but is not persuasive. The nature of the invention requires a reliable correlation between the expression level of TNFα, IL-6, CRP, IL-10, FABP, and PPY and (i) the presence of the proinflammatory endophenotype profile and a metabolic endophenotype and (ii) the responsiveness of AD subject to treatment with a PPAR-γ agonist. The claims state that (i) and (ii) can be determined based on the expression level of at least one of TNFα, IL-6, CRP, IL-10 AND at least one of FABP, and PPY. There is no evidence in the specification that this could actually be done. The examples in the specification teach over and over again that a 6-protein predictive biomarker algorithm was 100% accurate in identifying responder versus non-responder. The instant claims are much broader because they do not require all 6 proteins. It is maintained that further experimentation would be necessary to see if different combinations of two or more biomarkers would be successful for (i) identifying responders versus non-responders and for (ii) identifying subjects with the proinflammatory endophenotype profile and a metabolic endophenotype from subjects without the proinflammatory endophenotype profile and a metabolic endophenotype. Additionally since the claims encompass both mRNA and protein levels and the specification only provides support for protein levels and the prior art teaches that mRNA and protein levels are not concordant this would also have to be further investigated.
The response notes that the Office Action points to Wyeth v. Abbott Laboratories; Cephalon, Inc. v. Watson Pharm., Inc., citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc; and MPEP 2164.06(b) and In re Vaeck. They argue that the instant claims are distinct because the recite only six biomarkers. They also argue that the Office Action has failed to provide any evidence that a similar amount of work would be necessary to practice the claimed invention.
This argument has been fully considered but is not persuasive. The claims recite at least one of TNFα, IL-6, CRP, IL-10 AND at least one of FABP, and PPY. While there are only 6 biomarkers recited, there are actually greater than 45 different combinations recited in the claims. Further because the claims require determining if a subject is likely to respond to treatment with a PPAR-γ agonist, it is maintained that subjects would need to be monitored over the course of treatment which could be a long time.
Further it is noted that Applicants did not address some of the additional issues raised in the rejection. For example, 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. The enablement rejection is maintained.
It is noted for the record that amending the claims to recite the enabled subject matter indicated on page 5 would overcome this rejection.
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 require obtaining a blood, plasma, or serum sample; 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 instant claims require determining that a subject has both the proinflammatory endophenotype and the metabolic endophenotype based upon a comparison of at least one of IL-6, IL-10, CRP, and TNFa, and at least one of FABP and PPY, to a reference level. In contrast, the claims of the '840 Application recite a determining that the patient has a combination endophenotype profile based on the expression level of one or more biomarkers (claims 10 and 12) or each of the biomarkers (claim 13). As the claims of '840 Application are silent with respect to at least one of IL-6, IL-10, CRP, and TNFa, and at least one of FABP and PPY the Applicants argue the rejection should be withdrawn.
This argument has been fully considered but is not persuasive. The instant claims recite “at least one of IL-6, IL-10, CRP, and TNFa, and at least one of FABP and PPY”. This recitation encompass many different combinations of two or more biomarkers, including all of the biomarkers. The claims in the ‘840 application recite “one or more biomarkers” and “each” biomarker. This recitation encompass many of the same combinations of two or more biomarkers, including all of the biomarkers that is recited in the instant claims. For example the combination of IL-6 and FABP is anticipated by the ‘840 application where it recites one or more biomarkers selected grom the group consisting of the recited biomarkers which includes IL-6 and FABP. Thus the rejection is maintained.
10. 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.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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