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 .
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.
Status of the Claims
Claims 1 and 3-8 are pending; claim 1 is amended; claim 2 is canceled. Claim 8 is newly recited (previously claim 7 was recited in duplicate, the claims as amended omit the duplicate claim 7 and recite new claim 8).
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 1 and 3-8 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 as amended recites “determining a serological pattern of gluten immune reactivity and sensitivity comprising presence of the first antibody in the sample and absence of the second antibody from the sample”. Applicant indicates support for amendments to the claims (see remarks 09/24/2026, page 5) at paras [0045], [0054], [0057] of the published application. However, para [0045] supports indicating a serological pattern indicating gluten immune reactivity and sensitivity where the test results include positive results for IgG and/or IgA against mixed wheat proteins (i.e. whole wheat antigen), native α-gliadin, γ-gliadin, ω-gliadin, glutenin, deamidated glutenin, gluteomorphin, and wheat germ agglutinin, but not deamidated α-gliadin and not transglutaminase-2.
Para [0054] refers to a case report for a subject with gluten immune reactivity and sensitivity induced by a combination of Anesthetics, Antibiotics and Pain Medication, this subject tested for HLA typing and IgG and IgA anti-gliadin and anti-transglutaminase antibodies, the paragraph reports immunological tests showed these results: IgG anti-gliadin 6.8 U/mL (normal range <20 U/mL); IgA anti-gliadin 4.1 U/mL (normal range <20 U/mL); IgG anti-tTg 2.1 U/mL (normal range <6 U/mL); IgA anti-tTg 1.2 U/mL (normal range <4 U/mL); and negative for HLA DQ2 and DQ8. Para [0054] indicates, based on these findings gluten sensitivity and celiac disease were excluded, and it was concluded that the patient was suffering from psychogenic or idiosyncratic reaction associated with reaction to the anesthetic and its synergistic effect with the antibiotics
Claim 1 as amended encompasses determining gluten immune reactivity and sensitivity comprising presence of the first antibody and absence of the second (the open language comprising could encompass merely these two criteria, or these two criteria with additional criteria). Applicant’s specification does not support determining gluten immune reactivity and sensitivity based only on presence of first antibodies and absence of second antibodies (alone), as encompassed by the claimed language. The support indicated by Applicant appears to consider other additional criteria in order to determine immune reactivity and sensitivity, there does not appear to be support for relying on merely presence of first antibodies and absence of second antibodies, as claimed.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 3-4 and 6-8 are rejected under 35 U.S.C. 103 as being unpatentable over Aeschilmann et al., EP 1978364A1 in view of Rajadhyaksha et al., US Patent No. 6,703,208B1 (IDS entered 07/12/2024), Jones et al., Allergens, IgE, mediators, inflammatory mechanisms, J. Allergy Clin. Immunol., 95(3), (1995) p. 341-351, Cousins et al., WO03/046563A1 and Troncone et al., Coeliac disease and gluten sensitivity, Journal of Internal Medicine, 269, (2011), p. 582-590.
Aeschilmann et al. teach methods directed at diagnosis of autoimmune disorder characterized by presence of autoantibodies reacting with transglutaminase 6 (para [0011]), such as food sensitivity, namely gluten sensitivity (i.e., method of characterizing wheat sensitivity since a gluten sensitivity is considered to be a wheat sensitivity, including celiac disease). See specifically, the methods of Aeschilmann et al. comprises testing a sample (sera sample) obtained from the individual for antibody reactive to transglutaminase-2, antibody reactive to transglutaminase-3, and antibody to transglutaminase-6 (thereby addressing testing for a second, third and fourth antibody, as claimed, see para [0020] detection of transglutaminase 6 autoantibodies with detection of autoantibodies to one or more further transglutaminase isoforms, e.g., transglutaminase 2 and 3, and even more specifically see para [0031]-[0039]). See at para [0039], detection performed using ELISA, i.e., 96-well plate, 100µl/well of 5µl/well, wells contacted with portion of sample from individual, subsequently detected with ani-immunoglobulin antibody to determine presence of a first antibody reactive to the antigen coated at the well.
Aeschilmann et al. does teach (para [0003]) in susceptible individuals, consumption of gluten triggers a CD4+ T-cell response to gliadin as well as a B-cell response to gliadin and self-antigen. Aeschilmann et al. teach hallmark symptoms (of those affected) include weight loss, abdominal bloating, and pain and diarrhea as a consequence of the mucosal lymphocyte infiltration-triggered inflammation in the small bowel which may ultimately cause villous atrophy, Aeschilmann specifically teaching characteristically, the condition improves upon a gluten (wheat protein) exclusion from diet.
Aeschilmann et al. fails to teach in addition, also testing the sample for a first antibody reacted to mixed wheat antigen, the mixed wheat antigen a combination of water-soluble and alcohol-soluble proteins extracted from whole wheat. Further, as discussed fails to teach testing for mixed wheat antigen, and as such also fails to teach the method comprising preparing the mixed wheat antigen by combining water-soluble and alcohol soluble protein extracts prepared from whole wheat, the prepared mixture applied to the first test area (the first test site comprises an antigenic coating consisting essential of the water-soluble protein extract and the alcohol soluble protein extract).
Further, although Aeschilmann et al. teach patients are known to improve upon a gluten (wheat protein) exclusion from diet, Aeschilmann et al. fails to teach determining a pattern of gluten immune reactivity and sensitivity comprising presence of the first antibody (mixed wheat antigen solution) and absence of the second (antibody to TG2)the method comprising a step of administering a gluten free diet to the individual.
Rajadhyaksha et al. similarly teach detection of antibodies in sera of patients sensitive to gluten (i.e., those with celiac, see col. 1, lines 17-37, those that when exposed to gluten, have an immune system response that attacks the lining of the small intestine; see col. 2, lines 1-14, Rajadhyaksha teach detection antibodies to a combination of tTG (transglutaminase) and its substrates (gliadin (interpreted as native, i.e., not modified), glutenin, other peptides having multiple glutamines, see also col. 2, lines 18-28) for added sensitivity, as compared to methods that detect tTG alone). See Rajadhyaksha at Example 2 and Table 2, in addition to transglutaminase coated plates, microtiter wells are also included coated with α-gliadin, γ-gliadin or glutenin and further wells comprising a combination of γ-gliadin + glutenin (a mixed wheat antigen composition solution coated onto the wells of a microtiter plate).
Additionally, it is known in the prior art that the four major wheat protein fractions are albumin and globulin (protein species considered to be water soluble) and gliadin and glutenin (protein species considered to be water insoluble, alcohol soluble), see Jones et al., page 349, col. 2, para 4. Jones teach different fractions are important to different diseases, albumin found to be of primary importance for baker’s asthma, globulin in food hypersensitivity, and glutenin in celiac (also paragraph 4).
Cousins also teach an invention directed to the detection of antibodies which bind food allergens linked to food intolerance (see e.g., abstract). Cousins teach, regarding testing for antibody response to wheat, providing a composition comprising a combination of allergens, such as a combination of wheat allergen proteins (see page 2, lines 23-25). Regarding the wheat combinations, Cousins teach protein combinations inclusive of gliadins, glutenins, albumins and globulins, which see Jones, are proteins considered to all be the major fractions in whole wheat (gliadins and glutenins are proteins encompassed by Applicant’s claimed language “alcohol-soluble” and albumins and globulins are proteins encompassed by Applicant’s claimed language “water-soluble”).
The prior art at the time the claimed invention was effectively filed recognized that coeliac disease (CD) is considered more than a gluten-sensitive enteropathy, the art recognized that the common denominator for CD is presence of a variable combination of gluten-dependent clinical manifestations, specific autoantibodies (anti-TG2/anti-endomysium antibodies), HLA-DQ2 and/or DQ8 haplotypes and different degrees of enteropathy (see Troncone, page 582, col. 1, para 1). Troncone also teach gluten induces other pathological conditions (page 582, col. 1, para 2), see referring to gluten sensitivity, which encompasses sensitivities that miss one or more key CD criteria, but respond to gluten exclusion (col. 1 to col. 2). See page 587, col. 1, para 2, Troncone further refer to gluten sensitivity without anti-TG antibodies or enteropathy, that this condition has in common the regression of symptoms in response to a gluten-free diet in the absence of anti-TG antibodies and histological enteropathy.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention when performing a method assaying for a subject’s antibody response to wheat antigens to have modified the method of Aeschilmann et al. (the method for characterizing wheat sensitivity, comprising testing sample for antibodies to each of transglutaminase-2, 3 and 6), to further test the sample for antibodies reactive to mixed wheat antigen (i.e., to further prepare and subsequently add to the microtiter well plate, antigen that is combination of wheat antigens at a first test area, as taught by Rajadhyaksha et al.,) because Rajadhyaksha et al. teach methods for evaluation of patients reactive with gluten are more sensitive when tested for antibodies against transglutaminase and its substrates, as compared to transglutaminase alone. Therefore, one having ordinary skill would have been motivated to expand the detection method to detect also for antibodies reactive to mixed wheat antigen (antibodies to one or more substrates of tTG) in order to improve the sensitivity/specificity of the method, capturing a broader diagnostic value (since it is known for example, some patients with CD for example, only exhibit antibodies to deamidated peptide). One having ordinary skill in the art would have a reasonable expectation of success because the prior art recognized diagnosis of CD and gluten sensitivities as correlating with presence/absence of antibodies to the combination of tTG and one or more substrates of tTG, as well as deamidated peptides.
It would have been further prima facie obvious to one having ordinary skill in the art when including a test site for mixed wheat antigen, to have modified the wheat antigen mixture, to rely on a wheat antigen mixture consisting essentially of water soluble (such as albumin and/or globulin) and alcohol soluble (such as gliadin/glutenin) proteins (i.e., to have combined the water soluble and alcohol soluble extracts, the main protein fractions), such as in Cousins, as an obvious matter to try, namely by selecting from art recognized antigenic protein mixtures for screening for gluten sensitivity. In particular, it was known in the art to rely on mixture of gluten proteins (see as in Rajadhyaksha, preparing mixtures of wheat proteins, and Cousins, inclusive of mixture of all the known major gluten proteins). Further it was known that the major protein fractions specific to gluten were made up of albumin, globulin, gliadin and glutenin (Jones). One would have been motivated to rely on the mixture as in Cousins considering such a mixture contains all the major proteins, and because such a mixed antigen would be indicative of either of autoimmune disease (e.g., celiac) or hypersensitivity, as suggested by Jones.
Alternatively, the modification would be an obvious matter of a simple substitution of one art recognized wheat antigen mixture (Rajadhyaksha) for another (that of Cousins), both recognized in the art for detecting antibodies specific to gluten proteins, one motivated to rely on that of Cousins because it includes all the major wheat protein fractions (more complete).
One having ordinary skill in the art would have a reasonable expectation of success because the modification would necessarily still contain substrates to transglutaminase (which see as indicated above, Rajadhyaksha teach methods are more sensitive when tested for antibodies against transglutaminase and its substrates, as compared to transglutaminase alone). Additionally, one having ordinary skill in the art would have a reasonable expectation because such a mixture contains the major protein fractions of gluten, which the method is directed to determining sensitivity to gluten (Aeschilmann).
Further, it would have been prima facie obvious, upon performing the method as taught by the cited prior art, to have determined a serological pattern, and to have arrived at a determination of serological pattern of gluten immune reactivity and sensitivity upon the presence of first antibody (whole wheat protein extract) and absence of second antibody (to TG2) because it was recognized in the prior art that coeliac disease (CD) is considered more than a gluten-sensitive enteropathy, the art recognized that the common denominator for CD is presence of a variable combination of gluten-dependent clinical manifestations, specific autoantibodies (anti-TG2/anti-endomysium antibodies), the art recognizing gluten sensitivity similarly exhibit antibodies, except not those to transglutaminase- that both sensitivity and CD respond to a gluten free diet (Troncone). It was known that absence to transglutaminase-2 is a criteria distinguishing CD from gluten sensitivity (Troncone, see also Aeschilmann). It would have been obvious to have applied the method to distinguish between those patients/subjects having CD and those with sensitivity/reactivity.
One having ordinary skill in the art would have a reasonable expectation of success because this serological distinction is a pattern already known and recognized by those of ordinary skill in the prior art to distinguish CD from other gluten sensitivity diagnoses (Troncone).
Regarding the claim language “administering a gluten free diet to the individual”, it would have been further prima facie obvious to one having ordinary skill in the art, when detecting antibodies at the first through fourth portions (antibodies to the peptides) to further administer to that patient a gluten-free diet because it was known that patients exhibiting antibodies to peptides indicative of sensitivity (like peptides indicative of those with CD or non-CD gluten sensitivity) are known to improve upon a gluten (wheat protein) exclusion from their diet. The combination of the cited art above teaches detection of antibodies to a combination of peptides known to be indicative of someone who is reacting to a gluten diet, as a result it would be obvious, upon detection of antibodies to each of the portions indicated, to begin administration of a diet free of gluten. One having ordinary skill in the art would have a reasonable expectation of success because Aeschilmann et al. teach these patients are patients known to improve upon a gluten (wheat protein) exclusion from diet.
Regarding claims 3, 4 and 6, see Rajadhyaksha et al., for example at Example 2, Table 2, further teach testing antibodies, further relying on substrate comprising α-gliadin, γ-gliadin, and glutenin. As discussed above, Rajadhyaksha teach detecting antibodies to transglutaminase, as in combination with substrates of transglutaminase, improves sensitivity. It would have been further prima facie obvious to have modified the method of Aeschilmann to including testing of autoantibodies reactive to the additionally recited species in order to improve sensitivity, one having ordinary skill having a reasonable expectation of success for the reasons as discussed in detail previously above.
Regarding claim 7, the combination of the cited art teach detection of antibodies that are IgA type antibodies (see for example Rajadhyaksha, at Example 2).
Regarding claim 8, see as cited above, the prior art recognized CD is presence of a variable combination of gluten-dependent clinical manifestations, specific autoantibodies (anti-TG2/anti-endomysium antibodies), HLA-DQ2 and/or DQ8 haplotypes and different degrees of enteropathy (see Troncone, page 582, col. 1, para 1). It would have been prima facie obvious, when detecting first antibodies, and absence of second antibodies (see as discussed above), in those without CD to further determine HLA-DQ2/DQ8, and upon absence of this detection determine sensitivity and not CD because it was well known in the art at the time that HLA-DQ2 and/or DQ8 correlate with CD. One having ordinary skill in the art would have a reasonable expectation because it was known in the art (Troncone) that CD is presence of a variable combination of gluten-dependent clinical manifestations, which includes HLADQ2/DQ8 haplotypes.
Claim(s) 5 is rejected under 35 U.S.C. 103 as being unpatentable over Aeschilmann et al. in view of Rajadhyaksha et al., Jones et al., Cousins et al. and Troncone et al., as applied to claim 1 above, and further in view of Anderson et al. WO2005/105129A2.
The combination of Aeschilmann et al. and the cited prior art, teach a method substantially as claimed, but fails to teach further testing for autoantibodies to ω-gliadin (claim 5).
Anderson et al. also similarly teach methods comprising detection/presence of antibodies to particular epitopes as indicating gluten sensitivity (such as celiac see page 1, paragraph 2, coeliac disease caused by immune mediated hypersensitivity to dietary gluten, see further page 4, full paragraphs 3 and 4, gluten proteins encompass alpha/beta, gamma and omega gliadins, low and high molecular weight glutenins in wheat).
As cited previously above, Rajadhyaksha et al. similarly teach detection of antibodies in sera of patients sensitive to gluten (i.e., those with celiac, see col. 1, lines 17-37, those that when exposed to gluten, have an immune system response that attacks the lining of the small intestine; see col. 2, lines 1-14, Rajadhyaksha teach detection antibodies to a combination of tTG (transglutaminase) and its substrates (gliadin, glutenin, other peptides having multiple glutamines, see also col. 2, lines 18-28) for added sensitivity, as compared to methods that detect tTG alone). See Rajadhyaksha at Example 2 and Table 2, in addition to transglutaminase coated plates, microtiter wells are also included coated with α-gliadin, γ-gliadin or glutenin and further wells comprising a combination of γ-gliadin + glutenin (mixed wheat antigen).
It would have been further prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Aeschilmann et al. and the cited art to further test for antibodies against ω-gliadin to additionally improve sensitivity, one motivated to do so because, regarding evaluation of those patients reactive with gluten (i.e., those sensitive to exposure to gluten in their diet, such as those with celiac), Rajadhyaksha et al. teach methods are more sensitive when tested for antibodies against transglutaminase and its substrates, as compared to transglutaminase alone, and the art further recognized omega gliadins as specific epitopes for gluten hypersensitivity (celiac). Therefore, one having ordinary skill would have been motivated to expand the detection to the additional antibodies reactive (more antigens known to bind antibodies indicative of disease/disorder) in order to additionally improve the sensitivity of the method. One having ordinary skill in the art would have a reasonable expectation of success because the prior art recognized diagnosis as correlating with presence of antibodies to the combination of tTG and one or more substrates of tTG, and because the more tests indicative of the condition, the higher sensitivity one would expect in terms of detection.
Response to Arguments
Applicant's arguments filed 09/24/2026 have been fully considered but they are not persuasive for the following reasons.
Regarding the rejection of claims under 35 U.S.C. 103, Applicant refers to the amendments to the claims (see page 6) in order to overcome the previous rejections. Applicant summarizes the cited art, arguing that the cited art does not address the newly recited limitations (remarks pages 6-9). See new grounds of rejection set forth in detail above, addressing the amendments to the claims.
For these reasons, Applicant’s arguments are not persuasive and the claims are rejected as indicated above.
Conclusion
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLEN J MARCSISIN whose telephone number is (571)272-6001. The examiner can normally be reached M-F 8:00am-4:30pm.
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
