DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the claims
The amendment filed 08/11/26 is acknowledged and has been entered. New claims 38-43 have been added. Claims 2, 4, 6, 8-10, 13-16, 19, 32-33 and 36-37 were pending. Accordingly, claims 2, 4, 6, 8-10, 13-16, 19, 32-33 and 36-43 are under examination.
Withdrawn Rejections
All rejections of claims not reiterated herein, have been withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 40-41 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention. The claims are drawn to a an immunoassay for adiponectin (SEQ ID NO: 1) and IL-1RA (SEQ ID NO: 2) and any and all polymorphic sequence variants thereof in a sample from a pre-diabetic subject or a subject that has early-stage type 2 diabetes. The specification on page 8 discloses the measurement of serum adiponectin (SEQ ID NO: 1). The specification on page 8 discloses measuring the circulating levels of IL-1Ra (SEQ ID NO: 2). The examples on pages 13-14 are limited to the measurement of adiponectin and IL-1Ra. The specification does not disclose any and all polymorphic sequence variants of adiponectin and IL-1Ra and does not provide a single example of a variant of adiponectin or IL-1Ra measured in a pre-diabetic subject or a subject that has early-stage type 2 diabetes. Also, Applicant has not disclosed what portion of the adiponectin or IL-1Ra is critical of being displayed in a pre-diabetic subject or a subject that has early-stage type 2 diabetes. Applicant has not shown fragments of these markers which would provide the sensitivity and specificity to positively measured in this specific subject population. Further, antibodies which bind to all fragments of these markers are not known and conventional in the art. Thus, the scope of the claims include numerous structural variants thereof, and the genus is highly variable because a significant number of structural differences is permitted. Structural features which could distinguish the fragments in the genus from others in class are missing from the disclosure. No common structural attributed identify the members of the genus. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed. Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variable, the different lengths of amino acids is insufficient to describe the genus. A representative number of species for each genus must be disclosed to meet the written description requirement of 112 first paragraph. As set forth by the Court in Vas Cath Inc. V. Mahurkar, 19 USPQ2d 1111, the written description must convey to one of skill in the art “with reasonable clarity” that as of the filing date applicant was in possession of the claimed invention.
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 2, 4, 6, 10, 13, 36, and 38-42 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., (Pancreas, Vol 35, Number 1, July 2007, pages 16-21) in view of Pannala et al (Lancet Oncol 2009; 10, pages 88-95) and Goodson (US 2016/0231334) and further in view of Borrebaeck et al (US 9,863,960).
Chang et al discloses a method of the detection and differentiation of pancreatic ductal cancer and pancreatitis (e.g. abstract). Chang et al discloses that the method is for the early diagnosis of the pancreatic cancer (e.g. page 16). Chang et al discloses the method comprises obtaining a serum sample from a subject and detecting the level of adiponectin in the sample by enzyme-linked immunoassay (e.g. pg 17). Chang et al discloses comparing the level in the subject to that of a control (relevant matched control). Chang et al discloses that the levels in a pancreatic cancer subject is elevated compared to that of a pancreatitis subject and a control and that a pancreatitis subject to elevated compared to a control (e.g. pages 17-18 & Table 1). Chang et al shows that the adiponectin level in pancreatic cancer is 2-fold higher than that of a normal control (e.g. Table 1). Chang et al discloses that the control subjects showed no abnormality in routine blood tests, urine and stool occult blood test, chest radiograph examination and abdominal ultrasonography and were considered to be free of malignancy and CP (thus teaching healthy subject) (e.g. page 17). Chang et al also teaches the detection of CA19-9. Chang et al discloses that the CA19-9 is detected by immunoassay. Chang et al discloses the pancreatic carcinoma is ductal adenocarcinoma (e.g page 16). Chang et al discloses the method is for the early diagnosis of the ductal adenocarcinoma (e.g. page 16).
Chang et al differs from the instant invention in failing to teach the subject is asymptomatic.
Pannala et al teaches that pancreatic cancer has a dismal prognosis because cancer-specific symptoms occur only at an advanced stage and if the cancer is to be discovered early, screening will need to be done on asymptomatic individuals (e.g. abstract) and that this will include subject at high-risk and include to identify individuals with unique clinical phenotype, using one or more biomarkers of early pancreatic cancer (e.g. page 89). Pannala et al teaches the subject can have type -2 diabetes ( e.g. abstract, pgs 92-94).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate asymptomatic subjects and subjects with type-2 diabetes such as taught by Pannala into the method of Chang et al because Chang et al specifically teaches the method is for the early diagnosis of the ductal adenocarcinoma and Pannala et al teaches that pancreatic cancer has a dismal prognosis because cancer-specific symptoms occur only at an advanced stage and if the cancer is to be discovered early, screening will need to be done on asymptomatic individuals. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating asymptomatic subjects such as taught by Pannala et al into the method of Chang et al.
Chang et al and Pannala et al differ from the instant invention in failing to explicitly teach the antibody that binds to adiponectin.
Goodson teaches that it is known and conventional in immunoassay to use an antibody that specifically binds to adiponectin to provide for the detection of the complex (e.g para 0071).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate an antibody such as taught by Goodson into the method of Chang for the detection of adiponectin because Goodson teaches that it is well known, routine and conventional. Further, as is known in the art immunoassays implies an assay with the use of an antibody. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating an antibody such as taught by Goodson into the method of Chang for the detection of adiponectin.
Chang et al., Pannala et al and Goodson differ from the instant invention in failing to teach detecting IL-1Ra.
Borrebaeck et al teaches measuring the expression levels of biomarkers such as IL-1Ra in subjects with pancreatic cancer and comparing to a control to determine a difference (e.g. abstract, col’s 2-3, 31). Borrebaeck et al discloses that the IL-1Ra can be detected by use of immunoassay and antibodies (e.g col 15). Borrebaeck et al discloses that the expression level of IL-1Ra is up regulated (increased) in pancreatic cancer subjects compared to a normal control (e.g. col 9, lines 1-10). Borrebaeck et al discloses that the pancreatic cancer to be detected can be pancreatic ductal adenocarcinoma (e.g. col 10, lines 47-56).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate the detection of IL-1Ra such as taught by Borrebaeck et al in the modified method of Chang et al because Borrebaeck et al teaches that IL-1Ra is up regulated in subjects with pancreatic ductal adenocarcinoma. Further, one of ordinary skill in the art would understand that additional tests and assessments known to be correlated with pancreatic cancer would provide a more confident assessment of pancreatic cancer. It has long been held that it is obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose. In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Therefore, one of ordinary skill in the art would have a reasonable expectation of success incorporating the measurement of IL-1Ra such as taught by Borrebaeck et al in the modified method of Chang et al for the determination of pancreatic cancer.
With respect to the recitation “early stage pancreatic ductal adenocarcinoma or pancreatitis” as currently recited. Chang et al teaches that the method is for the early diagnosis (e.g. page 17) and although Chang et al is silent with respect to the stage as being early the combination of Chang et al., Goodson and Borrebaeck et al teach the detection of the same biomarkers in the same sample and the same steps as currently recited and therefore absent evidence to the contrary it is deemed that the modified method of Chang et al is detecting early stage pancreatic ductal adenocarcinoma or pancreatitis.
With respect to claim 36 as recited have the combination of references with Pannala et al teaches the subject can have type-2 diabetes.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., in view of Pannala et al., Goodson and Borrebaeck et al as applied to claims 2, 4, 6, 10, 13 and 36 above, and further in view of Illes et al (Pancreatology, 16, 2016, pages 266-271).
See above for the teachings of Chang et al., Pannala et al., Goodson and Borrebaeck et al.
Chang et al., Pannala et al., Goodson and Borrebaeck et al differ from the instant invention in failing to teach testing for diabetes mellitus and also fails to teach the control is from a positive diabetes negative pancreatic cancer control.
Illes et al teaches that it is known and conventional in the art that type-2 diabetes mellitus is widely considered to be associated with pancreatic cancer (e.g. abstract). Illes et al teaches that the prevalence of pancreatic cancer in patients with new-onset type-2 diabetes is significantly higher than that in the general population and that screening of these patients is beneficial for detecting pancreatic cancer in asymptomatic T2DM.
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate the testing of new onset type-2 diabetes mellitus in the subjects in the modified method of Chang et al because Illes etal shows that patients with new-onset type-2 diabetes is significantly higher than that in the general population and that screening of these patients is beneficial for detecting pancreatic cancer in asymptomatic T2DM. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating the testing of new onset type-2 diabetes mellitus in the subjects in the modified method of Chang et al.
It would have also been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate a positive diabetes mellitus with negative pancreatic cancer as a control because one of ordinary skill in the art would understand that this provides for a diagnosis of pancreatic cancer with reaffirmed assurance because one or ordinary skill in the art would recognize that both being increased in the sample indicates the subject as pancreatic cancer associated with diabetes.
Claims 14 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., in view of Pannala et al., Goodson and Borrebaeck et al as applied to claims 2, 4, 6, 10, 13 and 36 above, and further in view of Hess et al (US 2013/0122530) and Drum et al (US 2014/0011728).
See above for the teachings of Chang et al., Pannala et al., Goodson and Borrebaeck et al.
Chang et al., Pannala et al., Goodson and Borrebaeck et al differ from the instant invention in failing to teach the use of monoclonal antibodies for the detection of adiponectin and IL-1Ra.
Hess et al teaches that it is known and conventional in the art to use monoclonal antibodies specific for adiponectin for the detection of adiponectin (e.g. para 0248).
Drum et al teaches that it is known and conventional in the art to use monoclonal antibodies specific for IL-1Ra for the detection of IL-1Ra (e.g. para 0124).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate antibodies such as taught by Hess et al and Drum et al into the modified method of Chang et al for the detection of adiponectin and IL-1Ra because Hess et al and Drum et al show that it is known and conventional. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating antibodies such as taught by Hess et al and Drum et al into the modified method of Chang et al for the detection of adiponectin and IL-1Ra.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., in view of Pannala et al., Goodson and Borrebaeck et al as applied to claims 2, 4, 6, 10, 13 and 36 above, and further in view of Tummala et al (Journal of Gastrointestinal Oncoloy, Vol. 2, No. 3, September 2011, pages 168-174).
See above for the teachings of Chang et al., Pannala et al., Goodson and Borrebaeck et al.
Chang et al., Pannala et al., Goodson and Borrebaeck et al differ from the instant invention in failing to teach the subject is imaged.
Tummala et al teaches that it is known and conventional in the art to image a subject (e.g. abstract, page 172). Tummala et al teaches that this imaging provides promise in differentiating pancreatic cancer from pancreatitis (e.g page 172).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate imaging such as taught by Tummala et al into the modified method of Chang et al because Tummala et al shows that it is known and conventional in the art and provides for differentiating pancreatic cancer from pancreatitis. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating imaging such as taught by Tummala et al into the modified method of Chang et al.
Claims 16, 19 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., Pannala et al., in view of Goodson and Borrebaeck et al as applied to claims 2, 4, 6, 10, 13 and 36 above, and further in view of Conroy et al (The Ne England Journal of Medicine, Vol. 379, NO.25, December 2018, pages 2395-2406).
See above for the teachings of Chang et al., Pannala et al., Goodson and Borrebaeck et al.
Chang et al., Pannala et al., Goodson and Borrebaeck et al differ from the instant invention in failing to teach treating the subject once identified with the pancreatic cancer.
Conroy et al teaches that it is known in the art that surgery such as resection is the only chance of cure in pancreatic adenocarcinoma (e.g. pag 2396). Conroy et al also teaches chemotherapy with FOLFIRINOX which leads to longer overall survival (e.g. abstract, page 2403).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate resection and/or FOLFIRINOX into the modified method of Chang et al for treatment to a subject identified with pancreatic adenocarcinoma because Conroy et al teaches that surgery such as resection is the only chance of a cure and also teaches that therapy with FOLFIRINOX leads to longer overall survival. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating resection surgery and/or FOLFIRINOX therapy such as taught by Conroy into the modified method of Chang et al.
Claims 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al., in view of Pannala et al., Goodson and Borrebaeck et al as applied to claims 1-2, 4, 6, 10, 13 and 36 above, and further in view of Haab et al (US 2011/0257029).
See above for the teachings of Chang et al., Pannala et al., Goodson and Borrebaeck et al.
Chang et al., Pannala et al., Goodson and Borrebaeck et al differ from the instant invention in failing explicitly teach the use of a monoclonal antibody to bind the CA-19-9 for detecting the CA-19-9.
Haab et al teaches that it is known and conventional in immunoassay to use a monoclonal antibody that specifically binds to CA-19-9 to provide for the detection of the complex (e.g para 0071).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to incorporate an antibody such as taught by Haab et al into the method of Chang for the detection of Ca-19-9 because Chang et al specifically teaches that an immunoassay can be used for the detection and Haab et al teaches that it is well known, routine and conventional. Further, as is known in the art immunoassays implies an assay with the use of an antibody. Thus, one of ordinary skill in the art would have a reasonable expectation of success incorporating an antibody such as taught by Haab et al into the modified method of Chang for the detection of Ca-19-9.
Response to Arguments
Applicant's arguments filed 08/11/26 have been fully considered but they are not persuasive.
103 Rejections:
Applicant argues that although Borrebaeck et al. identify IL-1Ra as being present in samples from pancreatic cancer patients, this reference also identifies numerous other potential biomarkers. Column 8, line 65 to column 9, line 10 recites several different biomarkers (approximately 53) upregulated in pancreatic cancer. Table IV(A) (column 32) of Borrebaeck et al. identifies "core" biomarkers for the diagnosis of pancreatic cancer. Specifically, Borrebaeck et al. teach that interleukin 7 and integrin α-10 are core markers of pancreatic cancer. In Table IV(B), 12 additional biomarkers are identified as "preferred biomarkers" - none of which are IL-1Ra. Instead, IL-1Ra is only mentioned as an "optional" biomarker amongst numerous other biomarkers (Table IV(C)). The skilled person reading the teachings of Borrebaeck el al. would consider the core biomarkers as essential for the diagnosis of pancreatic cancer and, when considering the teachings of Chang et al., would combine interleukin 7 or integrin α-10 with adiponectin. However, there is no guidance that leads the skilled person to select IL-1Ra from the long list in Borrebaeck et al. and combine this marker with the detection of adiponectin as taught in Chang et al. Given the large list of potential biomarkers suggested in Borrebaeck el al., it would have required undue experimentation for a skilled person to specifically select the combination of adiponectin and Il- 1Ra.
This argument is not found persuasive because (1) 103 rejections are not based on the skilled artisan but rather one of ordinary skill in the art; and (2) The instant claims utilize open language and are not limited to only adiponectin and IL-1Ra and allow for panels of thousands of markers and one of ordinary skill in the art would recognize that a marker as shown by Borrebaeck et al such as IL-1Ra that is correlated with pancreatic cancer provides for further indication of pancreatic cancer and thus one of ordinary skill in the art would include IL-1Ra into the modified method of Chang et al. The instant claims allow for all the markers of Borrebaeck and thus one of ordinary skill releases that all markers of Borrebaeck are considered relevant and not just the preferred markers.
Applicant argues that none of Illes et al., Hess et al., Drum et al., Tummala et al., Haab et al and Conroy et al cure the deficiency of the combination of IL-1Ra with adiponectin.
This argument is not found persuasive because of reasons stated above that the combination of Chang et al., (Pancreas, Vol 35, Number 1, July 2007, pages 16-21) in view of Pannala et al (Lancet Oncol 2009; 10, pages 88-95) and Goodson (US 2016/0231334) and further in view of Borrebaeck et al (US 9,863,960) provides the combination of IL-1Ra with adiponectin and thus there is not a deficiency as argued by the applicant.
Applicant argues that the combination of adiponectin and IL-1Ra increases the reliability of identifying the relevant patient population, as demonstrated, for example, in Figure 5 of the application as filed. The data show that the use of these biomarkers in combination provides improved discrimination of patients with T3cDM compared with the use of either biomarker alone. This synergistic effect supports non-obviousness of the claimed methods. Figure 5 presents a receiver operating characteristic (ROC) curve illustrating the relationship between sensitivity (probability of detection) and the false positive rate (1-specificity). As shown, the combination of adiponectin and IL-1Ra provides improved identification of patients with T3cDM, i.e., diabetes resulting from pancreatitis or pancreatic cancer, compared with the use of adiponectin or IL-1Ra alone. In particular, the combined biomarker panel achieves a higher probability of correctly identifying T3cDM patients while reducing the false positive rate. This improvement is observed both in patients with new-onset diabetes and in patients previously diagnosed with T2DM
This argument is not found persuasive because the combination of Chang et al., (Pancreas, Vol 35, Number 1, July 2007, pages 16-21) in view of Pannala et al (Lancet Oncol 2009; 10, pages 88-95) and Goodson (US 2016/0231334) and further in view of Borrebaeck et al (US 9,863,960) disclose method steps, reagents and biomarkers consonant to the instantly recited claims and therefore absent evidence to the contrary it is deem that the instant claims would increase the reliability of identifying the relevant patient population. Also, as stated above the instantly recited claims recite method steps, reagents and biomarkers consonant to the instantly recited claims and the fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex Parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Conclusion
No claims are 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY W COUNTS whose telephone number is (571)272-0817. The examiner can normally be reached M-F 7:00-4:00.
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/GARY COUNTS/ Primary Examiner, Art Unit 1678
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