DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 26 December 2024 has been entered.
Status of Application, Amendments and/or Claims
3. The amendment dated 12/26/2024 is acknowledged and entered into record. Claims 36, 60 and 62 are amended. Claims 37 and 44 have been canceled. Claims 36, 40-41, 43, 47-48, 50-51, 55 and 59-65 are currently pending.
4. Claims 36, 40-41, 43, 47-48, 50-51, 55 and 59-65, drawn to a method of treating parkinsonism, comprising detecting bacterial CsgA in a sample, determining parkinsonism in the subject and administering a therapeutic, are being considered for examination in the instant application.
Rejections withdrawn
5. Upon consideration of amendment of independent claims 36, 60 and 62, the rejection of claims under 35 USC 103 are withdrawn.
6. Upon consideration of cancellation of claim 44, the rejection under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn.
7. Upon consideration of cancellation of claims 37 and 44, the rejection under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, fourth paragraph, is withdrawn.
8. Upon consideration of amendment of independent claims 36, 60 and 62, the rejections under double patenting are withdrawn.
New Rejections – necessitated by amendment
Claim Rejections - 35 USC § 112-Second paragraph
9. 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.
10. 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.
11. Claims 36, 40-41, 43, 47-48, 50-51, 55, 59-65 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 pre-AIA the applicant regards as the invention.
12. The limitation “A method …..consisting of” in claims 36, 60 and 62 is rejected as being indefinite. Claims 36, 60 and 62 recite consisting of 3-5 method steps. However, each of the steps implicitly includes other unrecited steps. For example, “receiving…sample...” can include collecting at a particular time; “detecting…CsgA in the sample…nucleic acid sequencing” would involve extracting DNA from the samples, preparing DNA library and starting a sequencing run; “determining….” could include preparing the sample for assay which requires setting up of the tubes, adding reagent, running the assay, comparing with reference controls, interpreting data, and so on. The term “consisting of” therefore, does not necessarily negate or exclude any other step that is not explicitly claimed. The claims fail to identify the metes and bounds of the related subject matter and how that could be ascertained in the stated invention. MPEP 2173.02(II) states that if the language of the claim is such that a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement, a rejection of the claim under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph, is appropriate. Given the structure of the claims, because each of the steps necessarily and implicitly involves multiple steps, the broadest reasonable interpretation of claims 36, 60 and 62 would be construed to be “comprising of” the method steps, and the same will be applied for art rejections during present examination until further clarification.
13. Claims 40-41, 43, 47-48, 50-51, 55, 59, 61 and 63-65 are rejected as depending from indefinite independent claims.
Claim Rejections - 35 USC § 112, 4th paragraph
14. 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.
15. 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.
16. Claims 43, 47, and 48 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, fourth 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.
17. Claim 43 further broadens the limitations of claim 36. Claim 43 recites “further comprising detecting …. reference sample”. However, claim 36 recites “A method…. consisting of” the claimed steps, which excludes any step not specified in the claim (emphasis added). Since claim 43 recites a further step “comprising detecting the bacterial CsgA in the reference sample”, claim 43 is therefore, broadening the scope of claim 36.
18. Claims 47 and 48 are rejected as depending from claim 43.
19. 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
20. 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.
21. 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.
22. Claims 36, 40-41, 43, 47-48, 50-51, 55, 59-65 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. 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 or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
23. Claims 36, 60 and 62, are directed to: “a method……consisting of” the recited steps (emphasis added).
24. The specification as originally filed does not provide adequate written description for “consisting of” the method steps, because the specification does not contemplate the narrowed limitation catered to “consisting of” the method. The instant specification teaches “consisting of” in association with products, for example: “a composition …consisting of…” (para 0019); “polypeptides …consisting of…”, etc. (para 0027, 0034, 0036). With respect to methods the specification uses the “comprising” language (for example, para 0006, 0008, 0029, 0034) However, that the methods of instant claims must also “consist of” the recited steps are not expressly asserted, nor does this flow naturally from the specification. Applicant is required to cancel the new matter in the response to this Office Action. Alternatively, applicant is invited to provide sufficient written support for the “limitation” indicated above. See MPEP 714.02 and 2163.06.
25. Claims 40-41, 43, 47-48, 50-51, 55, 59, 61, and 63-65 are rejected as depending from claims 36, 60 and 62 not providing adequate written description for reasons explained above.
Claim Rejections - 35 USC § 103
26. 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.
27. Claims 36, 40-41, 43, 47-48, 50-51, 55, and 59-61 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Chen et al. (Scientific Reports, 6: 1-10, 2016), in view of Kong et al US PGPB 20060167057, 7/27/2006 (IDS), Lindquist et al (WO 2010111516, 9/30/2010), Lu et al USPGPB 20120301433, 11.29.2012 and Evans et al, (Mol Cell 57: 1-23, 2015), and in further view of Agarwal et al (Front Mol Biosc 2: 1-10, 2015) and Keshavarzian et al (Movement Disorders 30: 1351-1360, 2015), as evidenced by Lionnet et al (Acta Neuropathol 135: 1-12, published online 10/16/2017), and ELISA Wikipedia (ELISA - Wikipedia, downloaded on 6/20/24, 12 pages).
28. The claims are directed to a method of treating parkinsonism consisting of receiving a stool sample, from a subject not having an identified genetic risk of parkinsonism, detecting bacterial (E. coli) CsgA in the sample by at least one recited method (nucleic acid sequencing, PCR, RT-PCR, qPCR), wherein the E. coli CsgA comprises an amino acid sequence of any of SEQ ID NOs: 1-5 or 8, determining the subject to have parkinsonism if the E. coli CsgA is at higher levels than a reference sample of a healthy or non-parkinsonism individual, and administering an amyloid inhibitor that inhibits E. coli amyloidogenic CsgA to the subject (claim 36); wherein: determining bacterial CsgA in the sample comprises detecting the presence and/or level of CsgA (claim 50); or an aggregate of the bacterial amyloid comprising CsgA (claim 41). Claims 43 and 51 recite a further comprising step of detecting a bacterial CsgA in the reference sample, wherein bacterial CsgA comprises presence and/or aggregate level of the CsgA (claim 48). Claim 55 recites the group of disorders included in parkinsonism and claim 59 recites that the subject is not predisposed to parkinsonism. Claim 60 recites a method of delaying or reducing onset of parkinsonism in a subject consisting receiving a stool sample from the subject, measuring bacterial (E. coli) CsgA levels, the CsgA comprising the recited sequence, comparing the level to a control level from a healthy individual, and administering an amyloid inhibitor that inhibits seeding or nucleation of synuclein aggregation by CsgA, wherein the parkinsonism is Parkinson’s disease or PD (claim 61). Claims 40 and 47 recite detecting the presence or level of a nucleic acid encoding CsgA in the sample.
29. Chen et al teach that amyloid protein in the microbiota influence the origin and maintenance of neurodegenerative disease (page 7, para 3). The reference teaches that aged rats (having gut neurons with alpha-synuclein (AS) deposits) exposed to curli-producing bacteria elicit increased neuronal AS in the gut and brain, compared to rats exposed to mutant bacteria (not able to make curli), or vehicle alone (abstract; page 7, Animals). The reference also teaches that CsgA is the key element of the bacterial amyloid protein curli (page 2, para 1), and that biofilms are formed from bacterial amyloid. Chen et al suggest that aggregation of AS in the intestinal gut before diagnosis of PD indicates that the initiation comes from the gut tissues (including intestine) (page 1, para 1). The reference teaches that oral administration of curli-producing bacteria in rats results in increased AS deposits in the hippocampus and striatum neurons of the brain (Fig. 1a; Results, para 1; Discussion, para 2). The reference also teaches that brain alteration of AS can be induced “through oral tissues and their rich innervation as well as via a hematogenous route” (Discussion, para 2), thus indicating a communication of the proteins between brain and gut (or extra-brain tissues). Chen et al therefore, establishes brain and gut communication and that curli-producing bacteria increase neuronal AS in the gut and brain.
30. Chen et al do not teach the method steps of detecting CsgA in a sample using the method as recited in claims 36 and 60.
31. Kong et al teach methods of diagnosing and treating CNS and amyloid related diseases, like Parkinson’s disease (PD) or Parkinonism (abstract; para 0038, 0107), wherein treatment of the subject having such diseases is done by administering a compound that inhibits or reduces amyloid fibril formation or deposition (amyloid inhibitor) (claim 25; para 0040, 0042, 0223, 0232). The reference teaches diagnostic methods comprising detecting the presence of amyloid in a sample of a subject, wherein such information (detection of presence) indicates that the subject is suffering from a disease (detect a disease) or has a “predisposition to a disease” (at risk for the disease) (para 0265, 0266). Kong et al teach that amyloid peptides can be evaluated in subject samples by using methods well known to one skilled in the art, like ELISA, quantitative immunoblotting (i.e., measuring levels), immunoassay etc. (para 0221). Even though Kong et al do not teach the step of detecting amyloid in healthy (reference) samples (as recited in claims 43, 51), the diagnostic step would require comparison with a reference sample that would obviously be obtained from a healthy individual. The reference is silent with regards to the presence or absence of a genetic risk of parkinsonism in the subject, therefore, can inherently be considered as not having an identified genetic risk of the disease (instant claim 36).
32. Chen et al or Kong et al, do not teach detection of CsgA and that CsgA comprises an amino acid sequence of any one of SEQ ID NOs: 1-5 or 8 (as recited in claim 36, 60).
33. Lindquist et al teach that bacterial curli polypeptides are associated with human disease (para 0027), wherein CsgA is the major subunit (para 0028). The reference teaches methods for detecting a CsgA peptide (para 0044), including using enzyme linked with detectable antibody (ELISA) (para 0051). The reference also teaches a CsgA protein of SEQ ID NO: 42 that is 100% identical to instant SEQ ID NO: 1 (see Appendix 1 submitted with previous Office Action), as well as sequences that are 100% identical to instant SEQ ID NO: 2 (Appendix 2), SEQ ID NO: 3 (Appendix 3), SEQ ID NO: 4 (Appendix 4), SEQ ID NO: 5 (Appendix 5), and SEQ ID NO: 8 (Appendix 6). The reference further teaches that the peptide is from E. coli and is amyloidogenic (para 004; claim 89).
34. Lu et al teach that Curli fibers are functional amyloids, which play an integral role in amyloidogenic or amyloid associated diseases like PD (para 0486, 0350), and Example 4 of the reference teaches the discovery of therapeutic anti-amyloid peptides for inhibiting curli and amyloid-beta amyloids (para 0485, 0486). The reference teaches CsgA as the major curli subunit polypeptide (para 0117), wherein CsgA of SEQ ID NO: 205 (para 0093; Fig 12A) is 100% identical to instant SEQ ID NOs: 1, 8 (Appendix i, vi). The reference also teaches polypeptides that are 100% identical to instant SEQ ID NOs: 2, 3, 4, 5 (Appendix ii-v). Lu et al teach treating subjects including those diagnosed with the disease and those having a genetic susceptibility (risk) to the disease (para 0146), (which implicitly suggests that subjects include those: (i) having an identified genetic risk, OR (ii) not having an identified genetic risk), comprising administering an anti-amyloid peptide (amyloid inhibitor) to the subject (para 0161, 0146) (instant claim 36). The reference teaches that anti-amyloid peptide can inhibit or decrease amyloid formation, and “inhibit in vitro and in vivo assembly of curli formation by bacteria” in a biological sample (para 0076, 0123, 0145, 0288), wherein CsgA is an amyloidogenic (forming amyloid fibers) curli polypeptide (para 0062; 0127, 0145), and wherein the sample can be stool that can be used for measuring gene expression levels (para 0145). Since Lu et al teach that therapeutic anti-amyloid peptides inhibit curli formation, the reference therefore, implicitly suggests higher levels of bacterial CsgA in a subject sample (used for treatment) than in a control sample.
35. Chen et al, Kong et al, Lindquist et al. or Lu et al do not teach that the amyloid inhibitor inhibits amyloidogenic CsgA and interacts with synuclein (claim 60).
36. Evans et al teach that curli comprises functional amyloids assembled by enteric bacteria during biofilm formation and colonization in host. The reference teaches that the non-amyloidogenic CsgC encoded by a csg (curli specific gene) operon was highly effective in inhibiting CsgA amyloid formation (amyloidogenic CsgA) and assembly of AS; and in the absence of CsgC, CsgA formed toxic intracellular aggregates (abstract; page 11, para 2), i.e., CsgC is an inhibitor of amyloidogenic CsgA. The reference also teaches that CsgC selectively inhibits PD associated AS amyloid formation, thereby showing that CsgC interacts with both CsgA and AS (Figures 5C, D; page 7, para 3; page 10, para 2, 4), and has a common “interaction motif in CsgA and α-synuclein” (page 8, para 1). The reference concludes that CsgC is a “highly effective and selective inhibitor of amyloid formation” (page 3, para 1), implying that it is an amyloid inhibitor.
37. Chen et al, Kong et al, Lindquist et al, Lu et al or Evans et al, do not teach methods of detecting CsgA using nucleic acid assays of claim 36, and detecting the presence or level of a nucleic acid encoding CsgA in the sample (claims 40, 47).
38. Agarwal et al teach that molecular diagnostics is a powerful method of detecting and diagnosing at an early stage of neurodegenerative diseases like PD, by use of biomarkers, and that altered expression of RNAs can be an attractive means for clinical diagnosis (Introduction, para 1, 3; page 2, col 2, para 1). Agarwal et al also teach that molecular diagnostics biomarkers for PD allow an early identification of the disease, and subsequent monitoring of “the effectiveness of neuroprotective therapies for PD” (page 4, col 2, para 3). Agarwal et al further teach measuring PD biomarkers using qRT-PCR, which would distinguish PD and healthy subjects (page 6, col 1, para 2). The reference teaches that the analysis of biomarkers in biological samples would be more cost-effective than the more expensive diagnostic imaging (page 6, col 1, para 2, 3).
39. Chen et al, Kong et al, Lindquist et al, Lu et al Evans et al or Agarwal et al do not teach nucleic acid assays using a stool sample in PD.
40. Keshavarzian et al teach that fecal samples of PD patients show significant difference in microbial population and gene as compared to healthy control (HC) subjects (Abstract; page 1353, col 2, para 2; Discussion, para 1; concluding para on page 1358). The reference teaches the detection of different genes from the DNA extracted from feces (page 1352, col 2, last para). The reference also teaches that changes in fecal microbiota can influence “PD pathology and disease course” (page 1358, last para). The reference states that dysbiosis (gut microflora imbalance) and conditions associated with it leads to a risk of developing PD, and suggests the need for further investigation (page 1358, para spanning cols 1 and 2).
41. Chen et al, Kong et al, Lindquist et al, Evans et al, Agarwal et al or Keshavarzian et al do not teach determination of parkinsonism in the subject, when the sample has a higher level of bacterial CsgA as compared to a reference sample (instant claim 36), although Lu et al alludes to this aspect (see para above). However, this is a mental step, which would obviously be performed after the detection of CsgA. Also, the said references do not explicitly teach comparing the sample CsgA levels to control level from a healthy individual (instant claim 60). However, this would obviously be performed after measuring CsgA in the sample to verify that the levels are appropriate for treating the subject by administration of an amyloid inhibitor. Additionally, as stated above, Lu et al suggest higher levels of bacterial CsgA in a subject sample (used for treatment) than in a control sample, indicating an implicit step of comparing the subject sample with control healthy levels.
42. Chen et al, Kong et al, Lindquist et al, Lu et al Evans et al, Agarwal et al or Keshavarzian et al do not explicitly teach delaying or reducing onset of parkinsonism in a subject (claim 60).
43. However, the limitation in the preamble of claim 60 is an intended use of the claimed method steps and does not receive patentable weight. MPEP 2111.02(II) states that “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. Here, the body of the claim sets forth all the steps and starting materials, and the preamble of the claim merely sets forth an intended use of the steps. Upon performing the steps recited in claim 62 (as taught or suggested by the combined cited art), one would have necessarily delayed or reduced onset of parkinsonism, absent any evidence to the contrary.
44. It would have been, therefore, obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention for using the concept that bacterial amyloid curli protein results in increased AS deposits in the intestinal gut and in the brain, indicating PD or increased risk of PD (parkinsonism) as taught by Chen et al, and modifying a method of treating parkinsonism comprising receiving a sample of a subject, detecting the presence or levels of amyloid using assays like ELISA, and treating using amyloid inhibitors as taught by Kong et al, by detecting/quantifying bacterial CsgA in view of Lindquist et al./Lu et al, and using CsgC as an amyloid inhibitor parkinsonian therapeutic in view of the teachings of Evans et al, wherein PD biomarkers would be a nucleic acid, which can be detected using nucleic acid assays in view of the teachings of Agarwal et al, and the sample for detection is stool in view of the teachings of Keshavarzian et al. The person of ordinary skill would have been motivated to assay the CsgA protein (detect and measure the levels) as it promotes AS deposits in the gut and brain, leading to a diagnosis of PD, indicating that PD can initiate from gut tissues (Chen et al). The person of ordinary skill would also have been motivated to study gut microbiota proteins as studies have shown a transfer of gut to brain via the vagus nerve and epithelial intestinal barrier in PD, as evidenced by Lionnet et al (Abstract; Introduction, col 1), wherein the gut (enteric) bacteria can produce functional amyloid curli protein and initiate PD pathology (Lionnet et al, page 4, col 2, para 2). The person of ordinary skill would further be motivated to use CsgC curli subunit as this has been shown to be highly effective and a selective inhibitor of PD associated AS amyloid formation, and can inhibit CsgA. Still further, the person of ordinary skill would have been motivated to use nucleic acid for detection, as it would provide an early diagnosis of the disease, and would be more cost-effective than the more expensive diagnostic imaging (Agarwal et al), and because changes in the “pathologies, biochemistries and genetics of patients” can provide a comprehensive information about the disease (Agarwal et al, page 3, col 1, para 2). Lastly, the person of ordinary skill would have been motivated to detect nucleic acid in a stool sample as fecal samples of PD patients show significant difference in microbial population and gene as compared to healthy control (HC) subjects, and changes in fecal microbiota can influence “PD pathology and disease course” (Keshavarzian et al). The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of the cited prior art references, before the effective filing date of the instant invention.
45. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
46. Claims 36, 40-41, 43, 47-48, 50-51, 55, and 59-61 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Chen et al. (2016), in view of Kong et al (2006), and Farlow et al, (GeneReviews® 5/24/2014 – abstract pages 1-2), in further view of Lindquist et al (2010), Lu et al (2012), Evans et al, (2015), Agarwal (2015) and Keshavarzian et al (2015).
47. NOTE: Although stated in the previous rejection, that the cited references can be construed as teaching that the subject is not having an identified genetic risk of the disease, the present rejection is based upon actual consideration of significance of genetic testing and risk prediction.
48. The teachings of Chen et al, Kong et al, Lindquist et al, Lu et al, Evans et al, Agarwal et al and Keshavarzian et al are set forth above.
49. Chen et al, Kong et al, Lindquist et al, Lu et al Evans et al, Agarwal et al or Keshavarzian et al do not explicitly state that the subject does not have an identified genetic risk of parkinsonism.
50. Farlow et al in a PD overview, teach that currently available genetic tests for the diagnosis of PD, “are not useful in risk prediction” for subjects with no family history of PD (or those with no identified genetic risk of PD) (Diagnosis/testing).
51. It would have been, therefore, obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention for using the concept that the bacterial amyloid curli protein results in increased AS deposits in the intestinal gut and in the brain, indicating PD or increased risk of PD (parkinsonism) as taught by Chen et al, and modifying a method comprising receiving a sample of a subject, detecting the presence or levels of amyloid using assays like ELISA, and treating the subject based upon Kong et al, and Farlow et al, by detecting bacterial CsgA as taught by Lindquist et al/Lu et al., using CsgC as an amyloid inhibitor parkinsonian therapeutic in view of the teachings of Evans et al, wherein the CsgA levels is a nucleic acid that can be detected using nucleic acid assays in view of the teachings of Agarwal et al, and the sample for detection is stool in view of the teachings of Keshavarzian et al. The person of ordinary skill would have been motivated to assay the CsgA protein as it promotes AS deposits in the gut and brain, leading to a diagnosis of PD, indicating that PD can initiate from gut tissues (Chen et al). The person of ordinary skill would have also been motivated to include a subject not having an identified genetic risk of parkinsonism in the instant diagnostic testing, as genetic identification is not a useful PD risk predictor in subjects with no family history of the disease (Farlow et al). The person of ordinary skill would have expected success because bacterial amyloidogenesis related to CNS diseases was known and investigated before the effective filing date of the instant invention.
52. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
53. Claims 62-65 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Chen et al. (2016), Kong et al (2006) (IDS), Lindquist et al (2010), Lu et al (2012) in view of Felden et al US 20160348102, 12/1/2016, Lagier et al (Clin Microbiol Rev 28: 208-236, Jan 2015) and Evans et al (2015), and in further view of Keshavarzian et al (2015).
54. The claims are directed to a method of improving motor deficit in a subject having parkinsonism comprising receiving a stool sample from the subject, measuring amyloid producing bacterial species level, and bacterial (E. coli) CsgA level produced by the species, and the E. coli CsgA comprises a sequence of any of SEQ ID NOs: 1-5 or 8, comparing the CsgA level to a control level from a healthy individual, and administering an amyloid inhibitor that inhibits the interaction of bacterial amyloidogenic CsgA with synuclein (claim 62); wherein: the amyloid producing bacterial species is Escherichia coli (claim 63); measuring the bacterial species level comprises culturing the bacteria in the sample (claim 64); and the administering improves tremors, muscle rigidity, bradykinesia or impaired gait (claim 65).
55. The teachings of Chen et al, Kong et al, Lindquist et al and Lu et al, are set forth above.
56. Lindquist et al further teach quantifying E. coli bacteria containing curli (para 0015) (instant claim 62).
57. Chen et al, Kong et al, Lindquist et al, Lu et al do not teach culturing of the bacterial species in the sample (instant claim 64).
58. Felden et al teach culturing of E. coli cells with curli and measuring bacterial CsgA expression and protein levels (Example 1, paras 0123, 0141, 0163) (instant claims 62-64). Even though the reference does not teach amyloid producing E. coli, this would be inherent as CsgA is the key element of the bacterial amyloid protein curli based upon teachings by other references in the cited art as stated above.
59. Lagier et al teach that bacterial culture under proper conditions will result in pure and large amounts of bacteria, allowing for genomic and proteomic studies to “highlight specific proteins”, and study their properties and antigenicity for diagnostic testing (Introduction, para 1; page 221, col 2, Cell Culture, para 2).
60. Chen et al, Kong et al, Lindquist et al. Lu et al, Felden et al or Lagier et al do not teach that the amyloid inhibitor inhibits amyloidogenic CsgA and synuclein interaction.
61. The teachings of Evans et al are set forth above.
62. Chen et al, Kong et al, Lindquist et al, Lu et al, Felden et al, Lagier et al, or Evans et al do not teach using a stool sample in PD.
63. The teachings of Keshavarzian et al are set forth above.
64. Chen et al, Kong et al, Lindquist et al, Lu et al, Felden et al, Lagier et al, Evans et al or Keshavarzian et al do not teach comparing the sample CsgA levels to a control level from a healthy individual. However, this will obviously be performed after measuring CsgA levels in the sample, to verify that the subject is appropriate for treatment. Additionally, as stated above, Lu et al suggest higher levels of bacterial CsgA in a test sample (from a subject used for treatment) than in a control sample, which implicitly would be derived following a comparison of the sample and control healthy levels.
65. Chen et al, Kong et al, Lindquist et al. Lu et al, Felden et al, Lagier et al, Evans et al. or Keshavarzian et al do not teach improving motor deficit (claim 62) or improving the symptoms as recited in claim 65.
66. However, the limitation in the preamble of claim 62 reciting “a method of improving a motor deficit…. parkinsonism”, is an intended use of the claimed method steps and does not receive patentable weight. MPEP 2111.02(II) states that “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. Here, the body of the claim sets forth all the steps and starting materials, and the preamble of the claim merely sets forth an intended use of the steps. Additionally, with respect to claim 65 reciting “wherein the administering improves tremors….... gait" is directed to a result of the method, but not a step that is to be performed by the artisan. Upon performing the steps as recited in claim 62, comprising receiving a sample from a subject having parkinsonism or PD, measuring CsgA and amyloid producing bacteria, comparing the subject and control levels of CsgA and administering an amyloid inhibitor, (taught by the combined cited art), one will necessarily have improved PD or parkinsonism symptoms listed in claim 65.
67. It would have been, therefore, obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention for using the concept that the bacterial amyloid curli protein results in increased AS deposits in the intestinal gut and in the brain, indicating PD or increased risk of developing PD (parkinsonism) as taught by Chen et al, and modifying a method for treating parkinsonism comprising receiving a sample of a subject, detecting and measuring the presence or levels of amyloid, and treating with amyloid inhibitors as taught by Kong et al, by detecting/quantifying bacterial CsgA in culture as taught in combination by Lindquist et al, Lu et al, Felden et al and Lagier et al, and using an amyloid (amyloidogenic CsgA) inhibitor in view of the teachings of Evans et al. and a stool sample for detection in view of the teachings of Keshavarzian et al. The person of ordinary skill would have been motivated to assay the CsgA protein (detect and measure the levels) as it promotes AS deposits in the gut and brain, leading to a diagnosis of PD, indicating that PD can initiate from gut tissues (Chen et al). The person of ordinary skill would also be motivated to use CsgC curli subunit as this has been shown to be highly effective and a selective inhibitor of PD associated AS amyloid formation, and can inhibit CsgA (Evans et al). The person of ordinary skill would have further been motivated to culture the bacteria in the sample as this will result in large amounts of bacteria in pure form, allowing for genomic and proteomic studies to “highlight specific proteins”, and study their properties for diagnostic testing (Lagier et al). Still further, the person of ordinary skill would have been motivated to use a stool sample, as fecal samples of PD patients show significant difference in microbial population and gene as compared to healthy control (HC) subjects, and changes in fecal microbiota can influence “PD pathology and disease course” (Keshavarzian et al). The person of ordinary skill would have expected success because bacterial amyloidogenesis related to CNS diseases was known and investigated before the effective filing date of the instant invention.
68. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
69. 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.
70. The applied reference has a common joint inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
71. This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
72. Claims 36, 40-41, 43, 47-48, 50-51, 55, and 59-61 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Sampson et al, US 20220040145, getting benefit of 5/15/2017 (filing date of provisional app 62/506457), in view of Lindquist et al (2010), Lu et al (2012), and in further view of Evans et al (2015).
73. Sampson et al teach methods comprising identifying and treating or preventing (delaying or reducing onset of) disorders like PD or parkinsonism associated with microbially-induced amyloid formation (Abstract; para 0003, 0043, claims 1-2, 7-9, 20), wherein the microbial amyloid comprises CsgA (para 0044, 0081; claim 8). The reference teaches determining (detecting) the presence or level of gut bacterial CsgA, or (measuring) the level of microbial organism producing CsgA in feces (stool) or intestinal sample of a subject using ELISA or nucleic acid assays like qualitative/quantitative PCR or sequencing (instant claims 40, 47) (para 0081, 0122), selecting or identifying (determining) that the subject has elevated levels of curli in the gut, and administering therapy (amyloid inhibitor) to the subject (para 0118, 0122) (instant claims 36, 41, 50, 55, 59, 60, 61). Even though Sampson et al do not teach the step of detecting amyloidogenic CsgA in healthy (reference) samples, the diagnostic step would require comparison with a reference sample that would obviously be obtained from a healthy individual. (instant claims 43, 48, 51). The reference is silent with regards to presence or absence of a genetic risk of parkinsonism in the subject, therefore, can inherently be considered as not having an identified genetic risk of the disease or not being predisposed to Parkinsonism. (instant claim 59)
74. Sampson et al do not teach CsgA having one of the sequences of SEQ ID NOs: 1-5 or 8.
75. The teachings of Lindquist et al and Lu et al are set forth above.
76. Sampson et al, Lindquist et al or Lu et al do not teach an amyloid inhibitor interacting with synuclein.
77. The teachings of Evans et al are set forth above.
78. It would have been, therefore, obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention for modifying a method comprising receiving a fecal sample of a subject, detecting the presence or levels of curli protein or CsgA by nucleic acid assays, and administering a therapy after determining elevated CsgA levels as taught by Sampson et al, wherein CsgA comprises a sequence identical to SEQ ID NOs: 1-5 or 8, which can be detected (or quantified) in view of Lindquist et al and Lu et al, and wherein CsgC is used as an amyloid (CsgA) inhibitor in view of the teachings of Evans et al. The person of ordinary skill would be motivated to use CsgC as this has been shown to be highly effective and a selective inhibitor of PD associated AS amyloid formation, and can inhibit CsgA (Evans et al). The person of ordinary skill would have expected success because bacterial amyloidogenesis related to CNS diseases was known and investigated before the effective filing date of the instant invention.
79. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
80. Claims 36, 40-41, 43, 47-48, 50-51, 55, and 59-61 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Sampson et al. (May 2017), in view of Farlow et al (2014), and in further view of Lindquist et al (2010), Lu et al (2012) and Evans et al, (2015).
81. The teachings of Sampson et al, Lindquist et al, Lu et al and Evans et al, are set forth above.
82. Sampson et al, Lindquist et al, Lu et al or Evans et al, are silent with respect to the subject not having an identified genetic risk of parkinsonism.
83. The teachings of Farlow et al are set forth above.
84. It would have been, therefore, obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention for modifying a method of treating parkinsonism comprising receiving a fecal sample of a subject, detecting the presence or levels of CsgA, and administering a therapy after determining elevated CsgA levels as taught by Sampson et al, and Farlow et al in combination, wherein CsgA comprises any of SEQ ID NOs:1-5 or 8, and can be detected using assays like PCR or ELISA in view of Sampson et al, Lindquist et al. and Lu et al, and wherein CsgC is used as an amyloid (CsgA) inhibitor in view of the teachings of Evans et al. The person of ordinary skill would have been motivated to include a subject not having an identified genetic risk of parkinsonism in the instant diagnostic testing, as genetic identification is not a useful PD risk predictor in subjects with no family history of the disease (Farlow et al). The person of ordinary skill would have expected success because bacterial amyloidogenesis related to CNS diseases was known and investigated before the effective filing date of the instant invention.
85. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
86. Claims 62-65 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Sampson et al. (May 2017), Lindquist et al (2010), and Lu et al (2012) in view of Felden et al (2016), Lagier et al (2015) and in further view of Evans et al (2015).
87. The teachings of Sampson et al and Lindquist et al and Lu et al are set forth above.
88. Sampson et al, Lindquist et al or Lu et al do not teach culturing of the bacterial species in the sample.
89. The teachings of Felden et al and Lagier et al are set forth above.
90. Sampson et al, Lindquist et al. Lu et al, Felden et al or Lagier et al do not teach that the amyloid inhibitor inhibits amyloidogenic CsgA and synuclein interaction.
91. The teachings of Evans et al are set forth above.
92. Sampson et al, Lindquist et al, Lu et al, Felden et al, Lagier et al or Evans et al do not teach comparing the sample CsgA levels to control level from a healthy individual (claim 62). However, this would obviously be performed after measuring CsgA in the sample to verify the levels before administration of an amyloid inhibitor. Moreover, Sampson et al teach that elevated levels of CsgA in the gut as compared to healthy controls correlate with PD (page 40, para 0332), indicating that a comparison with samples from healthy controls is necessary to confirm CsgA levels for diagnosis and treatment.
93. Sampson et al, Lindquist et al, Lu et al, Felden et al, Lagier et al or Evans et al do not explicitly teach improving motor deficit (claim 62) or improving the symptoms as recited in claim 65.
94. However, the limitation in the preamble of claim 62 reciting “a method of improving a motor deficit…. parkinsonism”, is an intended use of the claimed method steps and does not receive patentable weight. MPEP 2111.02(II) states that “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. Here, the body of the claim sets forth all the steps and starting materials, and the preamble of the claim merely sets forth an intended use of the steps. Additionally, with respect to claim 65 reciting “wherein the administering improves tremors….... gait" is directed to a result of the method, but not a step that is to be performed by the artisan. Upon performing the steps as recited in claim 62, comprising receiving a sample from a subject having parkinsonism or PD, measuring CsgA and amyloid producing bacteria, comparing the subject and control levels of CsgA and administering an amyloid inhibitor, (all taught by the combined cited art), one will necessarily have improved PD or parkinsonism symptoms listed in claim 65.
95. It would have been, therefore, obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention for modifying a method of treating parkinsonism comprising receiving a fecal sample of a subject, detecting the presence or levels of CsgA using assays like ELISA, and administering a therapy after determining elevated CsgA levels, in view of Sampson et al, by detecting/quantifying bacterial CsgA in culture as taught in combination by Lindquist et al, Lu et al, Felden et al and Lagier et al, and using an amyloid (amyloidogenic CsgA) inhibitor in view of the teachings of Evans et al. The person of ordinary skill would also be motivated to use CsgC curli subunit as this has been shown to be highly effective and a selective inhibitor of PD associated AS amyloid formation, and can inhibit CsgA (Evans et al). The person of ordinary skill would have further been motivated to culture the bacteria in the sample as this will result in large amounts of bacteria in pure form, allowing for genomic and proteomic studies to “highlight specific proteins”, and study their properties for diagnostic testing (Lagier et al). The person of ordinary skill would have expected success because bacterial amyloidogenesis related to CNS diseases was known and investigated before the effective filing date of the instant invention.
96. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
Applicant’s Remarks:
97. Applicant argues that the cited references, in combination or alone, fail to teach or suggest the method as recited in amended claims 36, 60 and 62 at least because 1) the reference combination does not teach all of the elements of claims 36, 60 and 62; and 2) Examiner relies on impermissible hindsight to reconstruct the claimed method by combining “disparate references without a clear motivation or predictable outcomes”. Asserting the amendment of claims reciting “consisting”, Applicant alleges that as the cited references “require additional features not recited in the claims” the references “do not teach or suggest the formulations recited in the present claims”. Listing the features recited as “consisting of” in instant amended claims, Applicant argues the teachings and deficiencies of each reference, for example emphasizing that the references do not teach the claimed nucleic acid assays. Applicant alleges that the teachings of Felden and Lagier are moot as the amended claims do not recite “ELISA or an in vitro culture”. Applicant asserts that the claims are used “as a roadmap to pick and choose different elements from different disclosures”. Applicant therefore requests the 103 rejections to be withdrawn.
98. Applicant’s arguments are fully considered. It is noted that previously made rejections have been withdrawn, and new rejections are set forth as necessitated by current amendment.
99. Applicant’s assertion about the amendment having “consisting” is not taught by the presently cited art, as these “require additional features not recited” is not persuasive. The amendment of claims 36, 60 and 65 is directed to “consisting” of a series of method steps, which is rendered as obvious by the combination of references, wherein each of the references teach or suggest the recited step/s. For instance: Chen teaches a connection between gut and brain, wherein the initiation comes from the gut tissues; Kong teaches detecting amyloid levels; Lindquist, Lu, Sampson and Evans teach detection of CsgA having the recited sequences and determining the need for treatment with an amyloid inhibitor when there is a higher level of bacterial CsgA as compared to control samples, and administering an amyloid inhibitor; Agarwal teaches RT-PCR assays for measuring PD biomarkers which is more cost-effective; Keshavarzian teaches the significance of using stool samples in PD; and Felden and Lagier teach culturing amyloid producing bacteria. That is, all the steps of instant claims 36, 60 and 62, in context with the knowledge that parkinsonism is a disorder associated with increased bacterial amyloidogenic CsgA that can be treated by administration of amyloid inhibitors, was known in the prior art of record. The preference for use of a stool sample, and assays for detection including nucleic acid assays were also taught in the cited art, and therefore, would be obvious to apply to the method of treatment. Applicant’s allegation that the cited references “do not teach or suggest the formulations recited in the present claims”, is moot as the claims do not recite any formulation. The teachings of the references in combination therefore, meets the requirement of instantly amended claims.
Please note that the broadest reasonable interpretation of claims 36, 60 and 62 would be construed to be “comprising of” the method steps, during present examination for reasons provided in para 12 of this Office Action.
100. Applicant’s argument that Felden and Lagier teachings are moot as the amended claims do not recite “ELISA or an in vitro culture”, is not persuasive. The references were used to only reject claims 62-65. Please note that claim 64 recites “culturing the amyloid-producing bacterial species”.
101. Applicant argues the teachings and deficiencies of each reference, on an individual basis. Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
102. Applicants may argue that the examiner's conclusion of obviousness is based on impermissible hindsight reasoning or using the claims as a roadmap to pick and choose different elements from different references. However, "[a]ny judgement on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant's disclosure, such a reconstruction is proper." In re McLaughlin 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971).
103. Applicant may also argue the use of a selective combination of disparate references without a clear motivation or predictable outcomes. However, there is no requirement that an "express, written motivation to combine must appear in prior art references before a finding of obviousness." See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004). The Supreme Court reaffirmed principles based on its precedent that "[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results. "Id. at 415-16, 82 USPQ2d at 1395. See MPEP § 2141 and § 2143 for guidance regarding establishment of a prima facie case of obviousness.
Double Patenting
Non-Statutory
104. 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).
105. 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).
106. 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.
107. 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.
108. Claims 36, 40-41, 43, 47-48, 50-51, 55, and 60-65 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-2, 4-10, 14, 16-17, and 19-20 of U.S. Patent No. 11,744,820, issued 5 September 2023, in view of Lindquist et al (2010), Felden et al (2016), Agarwal et al (2015) and Keshavarzian et al (2015).
Although the conflicting claims are not identical, they are not patentably distinct from each other because in each case the claims are drawn to a method comprising inhibiting or treating microbially induced amyloid disorder in a subject with intestinal bacterial amyloid aggregates comprising bacterial CsgA, like PD or parkinsonism, and detecting the presence or level of bacterial protein in an intestinal sample (i.e. a fecal sample – see col 20, lines 20-21 of ‘820 specification), wherein the subject for treatment is determined or selected if the bacterial protein level in the intestinal sample is greater than control (implying detecting in a control or reference sample of healthy or non-Parkinsonism), and administering an amyloid inhibitor.
The only differences between the 2 sets of claims are as follows:
(i) Instant claims 36, 60 and 62 recite CsgA comprising the sequences of any of SEQ ID NOs: 1-5 or 8, while the ‘820 patent claims do not recite any sequence. However, this would be obvious in view of Lindquist et al as stated above.
(ii) ‘820 claims do not recite the specific assays for detecting CsgA levels in fecal samples as recited in instant claims 36, 60, 62, or culturing the sample as in claim 64. However, this would be obvious in view of Lindquist et al, Keshavarzian et al and Felden et al for reasons stated above.
(iii) ‘820 claims recite specific compounds for inhibiting amyloid disorder in claim 1, while instant claims recite administering “an amyloid inhibitor”. However, paragraph 0033 of ‘820 PGPB teaches that the claimed compounds inhibit amyloid formation, therefore, are amyloid inhibitors. Instant claims are therefore, directed to an amyloid inhibitor genus.
(iv) Instant claims 60 and 62 recite measuring levels of CsgA and amyloid bacteria, while ‘820 patent claims are silent on this aspect. However, this would be obvious in view of the teachings of Lindquist et al.
(v) Instant claim 36 recites detection of CsgA using nucleic acid assays, while the ‘820 patent claims do not have this limitation. However, the use of assays like PCR would be obvious in view of the teachings of Agarwal et al for reasons stated above. Moreover, the ‘820 specification contemplates the use of qPCR for detection of CsgA in fecal sample (col 17, lines 10-13; Fig 4A; col 25, lines 18-19, 21-24).
109. Therefore, the instant claims are not patentably distinct over the issued claims in U.S. patent 11,744,820.
110. Claims 36, 40-41, 43, 47-48, 50-51, 55 and 60-65, are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-2, 5-10, 12, 21 and 25, of U.S. Patent No. 11,147,792, issued 19 October 2021, in view of Lindquist et al (2010), Felden et al (2016), Agarwal et al (2015) and Keshavarzian et al (2015).
Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims are directed to a method comprising inhibiting or treating microbially induced amyloid disorder in a subject with intestinal bacterial amyloid aggregates comprising bacterial CsgA, like PD or parkinsonism, and detecting the presence or level of bacterial protein in an intestinal sample (fecal sample – see col 20, lines 20-21 of ‘792 specification), wherein the subject for treatment is determined or selected if the bacterial protein level in the intestinal sample is greater than control (implying detecting in a control or reference sample of healthy or non-Parkinsonism), and administering an amyloid inhibitor.
The only differences between the 2 sets of claims are as follows:
i) Instant claims recite SEQ ID NOs: 1-5 or 8 for CsgA, while ‘792 patent claims do not recite any of the sequences. However, this would be obvious in view of Lindquist et al as stated above.
ii) ‘792 patent claims do not recite the specific assays for detecting CsgA levels in a fecal sample as recited in instant claim 36. However, this would be inherent as the ‘792 spec teaches detecting fecal CsgA levels using the instantly claimed methods including nucleic acid analysis (col 25, lines 10-44). The analysis of CsgA in culture of instant claim 64 would be obvious in view of Felden et al for reasons stated above.
(iii) Instant claim 36 recites detection of CsgA using nucleic acid assays, while the ‘792 patent claims do not have this limitation. However, the use of assays like PCR would be obvious in view of the teachings of Agarwal et al for reasons stated above.
iv) ‘792 patent claims recite specific compounds for inhibiting amyloid disorder in claim 1, while instant claims 36, 60 and 62 recite administering an amyloid inhibitor. However, column 6, lines 32-34, and the paragraph spanning columns 7 and 8, of ‘792 patent teaches that the claimed compounds inhibit amyloid formation, therefore, are inherently amyloid inhibitors. Instant claims are therefore, directed to an amyloid inhibitor genus.
v) Instant claims 36, 60 and 62 recite that the sample is stool, while ‘792 patent claims recite intestinal sample in claim 9. However, this would be obvious as the ‘792 patent (col 20, lines 18-30) teaches that intestinal sample like fecal sample is used for detection of CsgA.
(vi) Instant claims 60 and 62 recite measuring levels of CsgA and amyloid bacteria, while ‘792 patent claims are silent on this aspect. However, this would be obvious in view of the teachings of Lindquist et al.
111. Therefore, the instant claims are not patentably distinct over the issued claims in U.S. patent 11,147,792.
Applicant’s Remarks:
112. Traversing the rejections on the basis of amendment of claims to recite “consisting” of the steps, Applicant argues that the reference patent claims do not recite a specific combination of elements that consist of the recited steps. Applicant traverses the combination of the cited art with the reference patent claims for reasons set forth in the 103 discussion. Applicant therefore, requests withdrawal of the rejection.
113. Applicant’s arguments are considered, but not found to be persuasive for reasons presented in response to the remarks traversing the 103 rejections. The rejections have not been overcome by amendment or the filing of an approved terminal disclaimer. The rejections are therefore, modified as necessitated by amendment.
Conclusion
114. No claims are allowed.
115. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aditi Dutt whose telephone number is (571)272-9037. The examiner can normally be reached on M-F 9:00am-5:00pm.
116. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
117. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker, can be reached on 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
118. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/A. D./
Examiner, Art Unit 1675
12 March 2026
/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675