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 .
Claim Status
1. The amendment filed 09/30/2025 has been entered. Claims 1 – 5, 7 – 9, 11 – 13, and 15 – 19 remain pending and are under consideration. Claims 6, 10, 14, and 20 have been cancelled.
Priority
2. This application claims priority to French patent application FR 21/05293 filed on 05/20/2021.
Withdrawn Specification Objection
3. The objection to the specification is withdrawn in view of Applicant’s amendment to the specification to include trade mark symbols.
Withdrawn Claim Objections
4. The objection to claim 1 because of the following informalities: in line 4, “of a composition” should read “a composition” is withdrawn in view of Applicant’s amendment to the claim.
5. The objection to claim 1 because of the following informalities: in line 6, “the hypodermis” should read “hypodermis” is withdrawn in view of Applicant’s amendment to the claim.
6. The objection to claim 1 because of the use of periods at the end of each of step ia), ib), and ic) is withdrawn in view of Applicant’s amendment to the claim.
7. The objection to claim 1 because of the numbering of steps “ia”, “ib”, “ic”, and “ii”. Steps “ia”, “ib”, and “ic” should be numbered “(1a)”, “(1b)”, and “(1c)”; step “ii” should be numbered “(2)” is withdrawn in view of Applicant’s amendment to the claim.
8. The objection to claim 2 because of the following informalities: in line 1 – 2, “wherein step ia) consists of the subcutaneous injection” should read “wherein in step ia) the composition comprising the substance is administered by subcutaneous injection” is withdrawn in view of Applicant’s amendment to the claim.
9. The objection to claim 2 because of the following informalities: in line 2, “step ia)” should read “step (1a)” is withdrawn in view of Applicant’s amendment to the claim.
10. The objection to claim 3 because of the following informalities: in line 2, “step ib)” should read “step (1b)” is withdrawn in view of Applicant’s amendment to the claim.
11. The objection to claim 4 because of the following informalities: in line 2, “step ic)” should read “step (1c)” is withdrawn in view of Applicant’s amendment to the claim.
12. The objection to claim 5 because of the following informalities: in line 2, “step ic)” should read “step (1c)” and in line 4, “step 1a)” should read “step (1a)” is withdrawn in view of Applicant’s amendment to the claim.
13. The objections to claim 6 are rendered moot in view of Applicant’s cancellation of the claim.
14. The objection to claim 7 because of the following informalities: in line 2, “step id)” should read “step (1d)” is withdrawn in view of Applicant’s amendment to the claim.
15. The objection to claim 8 because of the following informalities: in line 2, “step ii)” should read “step (2)” is withdrawn in view of Applicant’s amendment to the claim.
16. The objection to claim 9 because of the following informalities: in line 2, “step ie)” should read “step (1e)” is withdrawn in view of Applicant’s amendment to the claim.
17. The objection to claim 10 is rendered moot in view of Applicant’s cancellation of the claim.
18. The objection to claim 11 because of the following informalities: in line 1, “step ib)” should read “step (1b)” is withdrawn in view of Applicant’s amendment to the claim.
19. The objection to claim 12 because of the following informalities: in line 1, “step ic)” should read “step (1c)” is withdrawn in view of Applicant’s amendment to the claim.
20. The objection to claim 13 because of the following informalities: in line 1, “step ic)” should read “step (1c)” is withdrawn in view of Applicant’s amendment to the claim.
21. The objections to the claim 14 are rendered moot in view of Applicant’s cancellation of the claim.
22. The objection to claim 15 because of the following informalities: in line 1, “step id)” should read “step (1d)” is withdrawn in view of Applicant’s amendment to the claim.
23. The objection to claim 16 because of the following informalities: in line 1, “step ii)” should read “step (2)” is withdrawn in view of Applicant’s amendment to the claim.
24. The objection to claim 17 because of the following informalities: in line 1, “step ie)” should read “step (1e)” is withdrawn in view of Applicant’s’ amendment to the claim.
25. The objection to claim 18 because of the following informalities: in line 1, “step ic)” should read “step (1c)” is withdrawn in view of Applicant’s amendment to the claim.
26. The objection of claim 19 because of the following informalities: in line 1, “step ic)” should read “step (1c)” and in line 3, “step ia)” should read “step (1a)” is withdrawn in view of Applicant’s cancellation of the claim.
27. The objections to claim 20 are rendered moot in view of Applicant’s cancellation of the claim.
Withdrawn Claim Rejections
33. The rejection of claim 1, 2, and 8 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to claim 1.
34. The rejection of claim 3 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to the claim.
35. The rejection of claim 5 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to the claim 1 and 5.
36. The rejection of claim 6 under 35 U.S.C. 112(b) is rendered moot in view of Applicant’s cancellation of the claim.
37. The rejection of claim 7 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to claim 1 and 7.
38. The rejection of claim 9 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to claim 1 and 9.
39. The rejection of claim 10 under 35 U.S.C. 112(b) is rendered moot in view of Applicant’s cancellation of the claim.
40. The rejection of claim 11 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to claim 1 and 11.
41. The rejection of claim 13 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to claim 1 and 13.
42. The rejection of claim 14 under 35 U.S.C. 112(b) is rendered moot in view of Applicant’s cancellation of the claim.
43. The rejection of claim 15 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to claim 1 and 15.
44. The rejection of claim 16 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to claim 1 and 16.
45. The rejection of claim 17 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to claim 1 and 17.
46. The rejection of claim 19 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to claim 1 and 19.
47. The rejection of claim 20 under 35 U.S.C. 112(b) is rendered moot in view of Applicant’s cancellation of the claim.
48. The rejection of clams 6, 10, 14, and 20 under 35 U.S.C. 101 is rendered moot in view of Applicant’s cancellation of these claims.
49. The rejection of claims 6, 10, 14, and 20 under 35 U.S.C. 103 are rendered moot in view of Applicant’s cancellation of these claims.
Maintained Claim Objections
50. Claim 1 remains objected to because of the following informalities: in line 1, “the inflammatory” should read “an inflammatory”. Appropriate correction is required.
51. Claim 1 remains objected to because of the following informalities: in line 2, “comprising the steps of” should read “comprising”. Appropriate correction is required.
52. Claim 1 remains objected to because of the following informalities: in line 5, “the epidermis, the dermis, and the skin” should read “epidermis, dermis, and skin appendages”. Appropriate correction is required.
53. Claim 1 remains objected to because of the following informalities: in line 7, “the inflammatory response” should read “an inflammatory response”. Appropriate correction is required.
54. Claim 1 remains objected to because of the following informalities: in line 9, “the level of mast cell degranulation of within” should read “a level of mast cell degranulation within”. Appropriate correction is required.
Claim Objections Necessitated by Amendment
55. Claim 1 is objected to because “TNFB” is repeated twice in step 1b. Appropriate correction is required. Appropriate correction is required.
56. Claim 1 is objected to because of the use of colons after “using”, “determining”, and “with” in lines 18, 23, and 28, respectively. Appropriate correction is required.
57. Claim 1 is objected to because of the following informalities: in line 2, “the allergic” should read “the associated allergic” because recitation of “the associated allergic” in line 26 lacks antecedent basis. Appropriate correction is required.
58. Claim 4 is objected to because of the use of a colon after “avidin” in line 3. Appropriate correction is required.
59. Claim 7 is objected to because of the use of a colon after “using” in line 3. Appropriate correction is required.
60. Claim 12 is objected to because of the use of a colon after “avidin” in line 3. Appropriate correction is required.
61. Claim 15 is objected to because of the use of a colon after “using” in line 3. Appropriate correction is required.
62. Claim 15 is rejected as it depends from cancelled claim 14. For the purpose of applying prior art, claim 15 is interpreted as depending from claim 13.
63. Claim 18 is objected to because of the use of a colon after “avidin” in line 3. Appropriate correction is required.
Claim Interpretation
64. For the purpose of applying prior art, “detecting and quantifying inflammatory markers” is interpreted as two markers from the those recited in lines 10 – 16 of claim 1.
65. For the purpose of applying prior art, low, moderate, and high degranulation of step 2 of claim 1 is interpreted as counting the number of granules around a mast cell based where low, moderate, and high granules are described in Applicant’s specification at page 16, para. 00096.
66. For the purpose of applying prior art, claim 9 is interpreted as measuring mast cell degranulation by measuring calcium ions in the presence of an agonist of MRGPRX2. Recitation of the “wherein” clause recites an intended use and is not given patentable weight.
Maintained Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
67. Claims 4, 12, and 18 remain rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Although maintained, note that the rejection is revised in view of the amendment to claims 4, 12, and 18 to recite “uses” instead of “utilizes”.
68. Regarding claim 4, it is unclear what is meant by “uses”. The specification at page 23, para. 000135 discloses labeling with flurochrome-conjugated avidin, however, this is not recited in the claim and no active steps are recited after “uses”. See MPEP 2173.05(q). For the purpose of applying prior art, claim 4 will be interpreted as measuring the amount of avidin binding to granules (see specification at page 15, para. 00089).
69. Regarding claim 12, it is unclear what is meant by “uses”. The specification at page 23, para. 000135 discloses labeling with flurochrome-conjugated avidin, however, this is not recited in the claim and no active steps are recited after “uses”. See MPEP 2173.05(q). For the purpose of applying prior art, claim 12 will be interpreted as measuring an amount of avidin binding to granules (see specification at page 15, para. 00089). Claim 13 is also rejected as it depends from claim 12 and does not clarify the grounds of rejection.
70. Regarding claim 18, it is unclear what is meant by “uses”. The specification at page 23, para. 000135 discloses labeling with flurochrome-conjugated avidin, however, this is not recited in the claim and no active steps are recited after “uses”. See MPEP 2173.05(q). For the purpose of applying prior art, claim 18 will be interpreted as determining the level of mast cell granulation by measuring an amount of avidin binding to granules (see specification at page 15, para. 00089).
Claim Rejections Necessitated by Amendment- 35 USC § 112(b)
71. Claims 1 – 5, 7 – 9, 11 – 13, and 15 – 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
72. Regarding claim 1, the phrase “such as” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claims 2, 4, 5, 7, 8, 9, 12, 13, and 15 – 19 are also rejected as they depend from claim 1 and do not clarify the grounds of rejection.
73. Regarding claim 1, recitation of “using” without any method steps recited thereafter renders the claim indefinite (see MPEP 2173.05(q)) because it is unclear how this use is actually practiced. It is unclear if more than one technique is required since the claim recites “techniques”. It is unclear what inflammatory mediators would be detected by colorimetric techniques or fluorescence techniques specific to mast cell granules. For the purpose of applying prior art, step 1c is interpreted as measuring the level of histamine, tryptase, lipids, cytokines, or chemokines with either a colorimetric or fluorescence technique based on Applicant’s specification at page 14, para. 00083. Claims 2 – 5, 7 – 9, 11 – 13, and 15 – 19 are also rejected as they depend from claim 1 and do not clarify the grounds of rejection.
74. Regarding claim 1, it is unclear in step 2 how to determine inflammatory potential because it is unclear if any increase in any inflammatory marker means the substance is inflammatory and if this is measured relative to administering a vehicle or if there is a threshold a substance being inflammatory. Claims 2 – 5, 7 – 9, 11 – 13, and 15 – 19 are also rejected as they depend from claim 1 and do not clarify the grounds of rejection.
75. Regarding claim 4, it is unclear what “in combination with a molecule that is complementary to avidin” means. It is unclear if this element only applies if an unconjugated avidin is used based on Applicant’s specification at page 15, para. 00089. If so, then as the claim requires a conjugated avidin, this element would not apply. For the purpose of applying prior art, claim 4 is interpreted as requiring measuring mast cell degranulation with avidin conjugated to a fluorophore.
76. Regarding claim 7, recitation of “using” without any method steps recited thereafter renders the claim indefinite (see MPEP 2173.05(q)) because it is unclear how this use is actually practiced. It is unclear if more than one technique is required since the claim recites “techniques”. It is unclear what inflammatory mediators would be detected by colorimetric techniques or fluorescence techniques specific to mast cell granules. For the purpose of applying prior art, step 1c is interpreted as measuring the level of histamine, tryptase, lipids, cytokines, or chemokines with either a colorimetric or fluorescence technique based on Applicant’s specification at page 14, para. 00083. Claim 8 is also rejected as it depends from claim 7 and does not clarify the grounds of rejection.
77. Regarding claim 12, it is unclear what “in combination with a molecule that is complementary to avidin” means. It is unclear if this element only applies if an unconjugated avidin is used based on Applicant’s specification at page 15, para. 00089. If so, then as the claim requires a conjugated avidin, this element would not apply. For the purpose of applying prior art, claim 12 is interpreted as requiring measuring mast cell degranulation with avidin conjugated to a fluorophore.
78. Regarding claim 15, recitation of “using” without any method steps recited thereafter renders the claim indefinite (see MPEP 2173.05(q)) because it is unclear how this use is actually practiced. It is unclear if more than one technique is required since the claim recites “techniques”. It is unclear what inflammatory mediators would be detected by colorimetric techniques or fluorescence techniques specific to mast cell granules. For the purpose of applying prior art, step 1c is interpreted as measuring the level of histamine, tryptase, lipids, cytokines, or chemokines with either a colorimetric or fluorescence technique based on Applicant’s specification at page 14, para. 00083. Claim 8 is also rejected as it depends from claim 7 and does not clarify the grounds of rejection.
79. Regarding claim 18, it is unclear what “in combination with a molecule that is complementary to avidin” means. It is unclear if this element only applies if an unconjugated avidin is used based on Applicant’s specification at page 15, para. 00089. If so, then as the claim requires a conjugated avidin, this element would not apply. For the purpose of applying prior art, claim 18 is interpreted as requiring measuring mast cell degranulation with avidin conjugated to a fluorophore.
Claim Rejections Necessitated by Amendment - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
80. Claims 3, 8, 11, and 16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
81. Regarding claim 3 that depends from claim 1, recitation of “at least two markers” does not further limit claim 1 because claim 1 recites “detecting and quantifying inflammatory markers” and the broadest reasonable interpretation of this recitation is more than one or at least two because “markers” is plural.
82. Claim 8 does not recite any positive, active method steps to further limit claim 7 and instead recites an intended use of “for further determining”. Therefore, claim 8 does not further limit claim 7.
83. Regarding claim 11 that depends from claim 2 which depends from claim 1, recitation of “at least two markers” does not further limit claim 2 because claim 2 depends from claim 1 and claim 1 recites “detecting and quantifying inflammatory markers” and the broadest reasonable interpretation of this recitation is more than one or at least two because “markers” is plural.
84. Claim 16 does not recite any positive, active method steps to further limit claim 15 and instead recites an intended use “for further determining”. Therefore, claim 16 does not further limit claim 15.
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.
Maintained Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
85. Claims 1 – 5, 7 – 9, 11 – 13, and 15 – 19 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to an in vitro method comprising abstract ideas (“determining” of steps 1b, 1c, 2) without significantly more. The claim(s) recite(s) “determining” and “using” (claim 1) and “uses” (claims 4, 12, 18), which are mental processes. Although the rejection is maintained, note that the rejection is revised in view of the amendment to the claims.
Claims 1 – 5, 7 – 9, 11 – 13, and 15 – 19 are drawn to an in vitro method for testing and determining simultaneously the inflammatory potential and the allergic or pseudoallergic potential of a substance without having to resort to an animal model, and comprising the steps of:
1a) administering to a skin explant, topically or by subcutaneous injection, a composition comprising the substance; where said skin explant comprises the epidermis, the dermis, and the skin appendages, as well as a thickness of at least 5 millimeters of hypodermis;
1b) determining the inflammatory response within the skin explant by detecting and quantifying inflammatory markers such as M-CSF, G-CSF, TNFSF6, IFNA2, IFNG, RANTES, MCP-3, MCP-2, CX3CL1, TNFA, TNFB, MIF, NAMPT, TRAIL and IFNAL TNFA, MCPL VEGF, IP-10, MDC, M1PlB, IL-17A, IL-17C, IL-17F, TNFB, IL-27, MCP-4, MIP-1A, IL-22, IL-1B, IL-12/IL-23p40, GM-CSP, IFNG, IL-12p70, IL-23, IL-31, EOTAXIN, IL-6, IL-4, IL-13, IL-5, IL-8, IL-15, BETA-HEXOSAMINIDASE, HISTAMINE, TRYPTASE, and CHYMASE;
1c) determining the level of mast cell degranulation of within the skin explant using: colorimetric techniques to measure the presence of inflammatory mediators contained in mast cell granules or secreted de novo, or fluorescence, immunofluorescence, or fluorochrome techniques specific to mast cell granules; and
2) determining the inflammatory potential of the substance with regard to an increase in inflammatory markers at the end of step 1b, and the associated allergic or pseudoallergic potential with regard to the proportions of mast cells undergoing low, moderate, or high levels of degranulation at the end of step 1c, with the substance presenting a low, or even zero, allergic or pseudoallergic potential if associated with a proportion of more than 50% of granulocytes exhibiting a low level of degranulation and/or less than 10% exhibiting a high level of degranulation; and the substance presenting a high allergic or pseudoallergic potential if associated with a proportion of more than 50% of granulocytes exhibiting a high level of degranulation.
The Office published Office's new guidance document entitled 2019 Revised Patent Subject Matter Eligibility Guidance, published January 7, 2019. Applicant is directed to the Federal Register, Volume 4, No. 4, pages 50-57 at page 74621.
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Step 1 of the USPTO' s eligibility analysis entails considering whether the claimed subject matter falls within the four statutory categories of patentable subject matter identified by 35 U.S.C. 101: Process, machine, manufacture, or composition of matter. The claims are directed to a process (step 1, Yes).
Step 2A of the 2019 Revised Patent Subject Matter Eligibility Guidance is a two-prong inquiry. In Step 2A Prong One, examiners evaluate whether the claim recites a judicial exception. The process is directed to abstract ideas of “determining the inflammatory response”, “determining the level of mast cell granulation”, and “determining the inflammatory potential” which fall into the “mental process” groupings of abstract ideas (Step 2A, prong 1, Yes). The claims recite a single active step of administering a substance to a skin explant followed by three steps that recite “determining”, which can be performed in the human mind. Support for “determining” as a mental process is found in the specification at page 23, para. 000138 that states “results permitted the determination” of mast cell granulation and inflammatory potential. While the specification discloses in Example 3 methods steps of detecting cytokines and mast cell granules, these steps are not recited in the claims. Therefore, the claimed process is directed to mental process groupings of abstract ideas and thus recites a judicial exception.
In Step 2A Prong Two, examiners evaluate whether the claim recites additional elements that integrate the exception into a practical application of that exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. The claim recites “for testing and determining simultaneously inflammatory potential and the allergic or pseudoallergic potential of a substance without having to resort to an animal model. An evaluation of whether this recitation is insignificant extra-solution activity is then performed. Note that because Step 2A Prong Two analysis excludes consideration of whether a limitation is well-understood, routine, conventional activity, this evaluation does not take into account whether or not the limitation is well-known. When so evaluated, this additional element is insignificant extra-solution activity because “determining” is again a mental process and the claim recites “substance” at a high level of generality, and no active method steps are recited regarding performing steps to measure inflammatory response or mast cell degranulation apart from “using” (see MPEP 2173.05(q)(I)) various “techniques”. Therefore, the intended use of the method fails to meaningfully limit the claim because it is at best the equivalent of merely adding the words “apply it” to the judicial exception. Accordingly, the intended use does not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception (Step 2A, prong 2, No).
In Step 2B, the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements adds an inventive concept into the claim. As discussed with respect to Step 2A Prong Two, the claim does not require any particular substance and is at best the equivalent of merely adding the words “apply it” to the judicial exception. Mere instructions to apply an exception cannot provide an inventive concept. At Step 2B, the evaluation of the insignificant extra-solution activity consideration takes into account whether or not the extra-solution activity is well-known. Here, recitation of “substance” is recited at a high level of generality. Thus, recitation of “substance” does not amount to significantly more and does not provide an inventive concept (Step 2B: No).
Limitations that were found not to be enough to qualify as ‘‘significantly more” when recited in a claim with a judicial exception include: Adding the words ‘‘apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer; simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well-understood, routine and conventional activities previously known to the industry; adding insignificant extrasolution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea; or generally linking the use of the judicial exception to a particular technological environment or field of use.
Maintained 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.
86. Claim(s) 1 – 5, 7 – 9, 11 – 13, and 15 – 19 remain rejected under 35 U.S.C. 103 as being unpatentable over Genoskin (WO2019063122A1; Filed 09/25/2018; Published 04/04/2019; previously cited), hereinafter Genoskin which is cited on the IDS filed 11/20/2023 in view of Gaudenzio (Gaudenzio, Nicolas, et al. The Journal of clinical investigation 126.10 (2016): 3981-3998; previously cited), hereinafter Gaudenzio which is cited on the IDS filed 11/20/2023. US12071648B2 is being used as the English translation of Genoskin. Although maintained, note that the rejection is revised in view of Applicant’s amendment to the claims. The Supplemental Materials of Gaudenzio is provided as this was not part of Applicant’s provided Gaudenzio prior art.
Regarding step 1a of claim 1 and claim 2, Genoskin teaches an in vitro method comprising subcutaneous injection (“subcutaneous injection” of step 1a of claim 1 and claim 2) of an activation solution (“substance” of step 1a of claim 1) into a skin biopsy comprising the epidermis, dermis, epidermal appendages, and hypodermis where the biopsy has a thickness of 1 cm (“skin explant” of step 1a of claim 1) (col. 4, lines 40 – 52; col. 7, lines 57 – 60; col. 8, lines 9 – 15; col. 20, lines 37 – 41 and 45 – 53).
Regarding step 1b and 2 of claim 1 and claims 3 and 11, Genoskin teaches measuring secreted pro-inflammatory cytokines IL-17A and IL-22 (“at least two” and “IL-17A” and “IL-22” and “increase in inflammatory markers at the end of step 1b” of step 1b and 2 of claim 1 and “at least two” and “IL-17A” and “IL-22” claims 3 and 11) (col. 22, lines 46 – 51; Figure 4; col. 5, lines 8 – 9; col. 23, lines 24 – 56). Genoskin teaches measuring IFNG and TNFA (col. 23, lines 24 – 56).
Genoskin does not teach “determining the level of mast cell granulation” of step 1c or step 2 of claim 1 or “uses avidin” of claim 4, 12, and 18, or “carried out within a maximum period of 6 hours” of claim 5, 13, and 19, or step 1d of claims 7, 8, 15, and 16, or step 1e of claim 9 and 17. However, Genoskin teaches the skin biopsies comprise mast cells by measuring Tryptase (col. 22, lines 14 – 21; Figure 3). Genoskin teaches there is a real need to develop ex vivo models of inflamed human skin and culture conditions of ex vivo skin samples suitable for use in inflammation modeling (col. 3, lines 44 – 51). Genoskin teaches the method provides an ex vivo model of inflamed skin which reflects more precisely and reproducibly the environment of the inflamed skin as observed in vivo in a physiopathological context (col. 3, lines 57 – 61).
Regarding “determining the level of mast cell granulation” of step 1c and step 2 of claim 1 and “uses avidin” of claims 4, 12, and 18, and “carried out within a maximum period of 6 hours” of claim 5, 13, and 19 and step 1d of claims 7, 8, 15, and 16, Gaudenzio teaches measuring mast cell degranulation by adding stimulants at different concentrations (“different concentrations of the substance” of claims 7, 8, 15, and 16) and 30 to 60 minutes later (“carried out within a maximum period of 6 hours” of claim 5, 13, and 19) adding Alexa-488-coupled avidin (“uses avidin conjugated to a fluorochrome” of claims 4, 12, 18) and measuring fluorescence using flow cytometry (“fluorescence” of step 1c and step 2 of claim 1) (page 3981, right col. last paragraph; page 3982, left col. paragraph 1; Figure 1; Supplemental Methods page 10, paragraph 2; page 11, paragraph 2, page 12, paragraph 1, and page 13, paragraph 2; Supplemental Figure 2). Gaudenzio teaches measuring cytokine secretion by the degranulating stimuli in Figure 1 where SP treatment causes an increase in MCP-1 at 30 min; anti-IgE causes an increase in VEGF and MCP-1 at 30 min; anti-IgE causes an increase in TNFA, IL-13, GM-CSF, VEGF, and MCP-1 at 90 min (“an increase in inflammatory markers at the end of step 1b” of claim 2) (Supplemental Methods page 9, paragraph 3). Gaudenzio teaches a time-dependence increase in degranulation where no granule structures are observed at 6 min with anti-IgE or at 1.5 min with SP (“low” of step 2 of claim 1); 4 – 6 granule structures form at 9 min with anti-IgE or at 3 min with SP (“moderate” of step 2 of claim 1), and more than 6 granules at 15 min for anti-IgE and 6 min for SP (“high levels” of step 2 of claim 1) (Figure 2A).
Regarding step 1e of claims 9 and 17, Gaudenzio teaches measuring mast cell intracellular calcium influx and degranulation dynamics mediated by MRGPRX2 with SP that is a strong activator of MRGPRX (Abstract; page 3982, left col. and right col. para. 1; page 3983, left col. para. 3; page 3991, right col. para. 2; Supplemental Methods page 42, last para.; Supplemental Methods page 43, para. 3; Figure 3; Supplemental Figure 3). Gaudenzio teaches in vivo measuring MRGPRB2 (mouse homolog of MRGPRX2) activation upon intradermal challenge with SP (page 3989, left col. para. 1; Figure 7; Supplemental Figure 13 – 14).
Gaudenzio teaches mast cell degranulation can contribute to the morbidity and mortality associated with allergic diseases (page 3981, left col. paragraph 1). Gaudenzio teaches stimuli that can activate mast cells via various receptors that are distinct from those binding antibodies also can contribute to inflammatory processes (page 3981, left col.). Gaudenzio teaches technical constraints have limited the spatiotemporal resolution of mast cell degranulation which has hampered analysis of the dynamics and quantitative characteristics of granule exteriorization in real time at the single-cell level (page 3981, right col. paragraph 2). Gaudenzio teaches the method for human primary mast cells in vitro can respond to distinct stimuli of activation by finely regulating the dynamics and features of mast cell granule secretion (page 3981, right col. paragraph 2). Gaudenzio teaches the dynamic imaging system can follow in real time the spatially complex, rapidly evolving features of mast cells undergoing activation and the method can be used to determine mast cell activation in vivo with intradermal injections (page 3981, right col. para. 2; Figure 6; page 3987, right col.; page 3989, left col. para. 1). Gaudenzio teaches their findings offer new ways to think about old clinical observations because their findings indicate that IgE-dependent and MRGPRX-2-dependent mast cell activator elicit patterns of mast cell degranulation that differ in spatiotemporal features and in the physical characteristics of the released granule structure and thus may contribute to differences in the clinical features of such reactions (page 3993, right col. last para. ; page 3994, left col.). Gaudenzio teaches it has been recognized clinically that the features of pseudoallergic reaction such as those known to activate MRGPRX2 can differ from those induced by the injection of allergens into the skin of sensitized subjects (which results in the IgE-dependent activation of cutaneous mast cells at that site) (page 3993, right col. last para.). Gaudenzio teaches pseudoallergic skin reactions are often transient whereas IgE-dependent cutaneous reactions can be longer-lasting where the persistence of inflammation at sites of IgE-dependent mast cell activation generally has been attributed to the effects of de novo synthesized mast cell mediators such as lipid mediators and cytokines (page 3993, right col. last para.).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Genoskin regarding an in vitro method of measuring inflammation of a substance subcutaneously injected into a skin biopsy comprising mast cells with the teachings of Gaudenzio regarding measuring mast cell degranulation to arrive at the claimed method for testing and determining simultaneously the inflammatory potential and the allergic or pseudoallergi potential of a substance without having to resort to an animal model. One would have been motivated to combine the teachings of Genoskin and Gaudenzio in a method to test the inflammatory potential and allergic or pseudoallergic potential of a substance in a skin explant as Genoskin teaches there is a real need to develop ex vivo models of inflamed human skin and culture conditions of ex vivo skin samples suitable for use in inflammation modeling and Gaudenzio teaches mast cell degranulation can contribute to the morbidity and mortality associated with allergic diseases and Gaudenzio teaches technical constraints have limited the spatiotemporal resolution of mast cell degranulation which has hampered analysis of the dynamics and quantitative characteristics of granule exteriorization in real time at the single-cell level. One would have a reasonable expectation of success in combining the teachings as Genoskin teaches the method provides an ex vivo model of inflamed skin comprising mast cells which reflects more precisely and reproducibly the environment of the inflamed skin as observed in vivo in a physiopathological context and Gaudenzio teaches the method for human primary mast cells in vitro can respond to distinct stimuli of activation by finely regulating the dynamics and features of mast cell granule secretion and Gaudenzio teaches the dynamic imaging system can follow in real time the spatially complex, rapidly evolving features of mast cells undergoing activation and the method can be used to determine mast cell activation in vivo with intradermal injections.
Applicant’s Arguments/ Response to Arguments
87. Applicant Argues: On page 9, para. 1 – 4 and 6 – 7 and page 10, para. 2 – 5, Applicant disagrees with the objection to claim 1 regarding “the inflammatory”, “comprising the steps of”, “the epidermis, the dermis, and the skin appendages”, “the inflammatory response”, and “the level of mast cell degranulation”.
Response to Argument: The objection to claim 1 is maintained. These recitations lack antecedent basis and the suggested corrections are to overcome antecedent problems. See MPEP 2173.05(e).
Applicant Argues: On page 16, para. 7 – 9, Applicant disagrees with the rejection of claims 4, 12, and 18 under 35 U.S.C. 112(b) because recitation of “utilizes” and Applicant asserts that use of avidin for determining the level of mast cell degranulation is a general knowledge of the skilled person as illustrated in the specification.
Response to Argument: Recitation of “utilizes” in claims 4, 12, and 18 has been replaced with “uses”. Recitation of “uses” without any active positive steps delimiting how the use is actually practiced renders the claim indefinite. The claims refer to step 1c or claim 1 but claim 1 also recites “using” and generally recites “techniques”. Therefore, the claims are indefinite as to how avidin is used. Further, the claims are rejected under 35 USC 101 for recitation of “uses” and “using” as explained in MPEP 2173.05(q).
Applicant Argues: On page 19, para. 8 – 10 and pages 20 – 23, Applicant disagrees with the rejection of the claims under 35 USC 101. Applicant asserts that the claimed process is not merely an abstract idea but a practical, technical application of specific steps that produce a concrete and tangible result. Applicant asserts that the method applies a Law of Nature in a technological context but is not limited to such law of nature. Applicant asserts that the steps of the invention include contacting a composition comprising the substance with a skin sample, detecting the inflammation markers, mastocytes cells degranulation, and MRGPRX2 activation and correlating the observed signals where the correlation involves technical interpretation of the data.
Response to Argument: The rejection is maintained because the claim recites “determining” and “using” and “determining” is a mental process and no active steps are recited after “using”. Step 2 of amended claim 1 is a mental process and Applicant asserts as much on page 22, last bullet point. Should Applicant amend “determining” and “using” to active steps such as “measuring”, the rejection may be overcome upon further consideration.
Applicant Argues: On page 23, para. 6 - page 27, Applicant disagrees with the rejection of the claims over Genoskin in view of Gaudenzio because the analysis is simplifying and reductive, the Genoskin model is not an inflammation model but is a constitutive inflammation skin model particularly psoriasis, the model of the invention is not an inflammation model but a detection and quantification inflammatory, together with allergic or pseudoallergic responses model, Genoskin neither describes nor teaches it is possible to successfully induce multiple and distinct stages of inflammation in a skin explant in culture or induce strong or weak inflammatory stages reaction and thus the skilled person has no suggestion or incitation to develop the method of claim 1 in view of Genoskin.
Response to Argument: This is not found convincing because the claims do not limit the skin explant apart from comprising epidermis, dermis, skin appendages, and a thickness of at least 5 mm of hypodermis, nor does the claim limit the substance and Genoskin teaches a method of preparing skin biopsies and administering a substance to the skin biopsies and measuring cytokines as markers of inflammation (col. 20, lines 25 – 61; col. 22, lines 45 – 60). Further, Genoskin teaches an untreated healthy skin biopsy (NativeSkin®) can be inflamed by cultured in the presence of a substance (col. 5, lines 8 – 19; Figure 4). Genoskin teaches there is a real need to develop ex vivo models of inflamed human skin and culture conditions of ex vivo skin samples suitable for use in inflammation modeling and Gaudenzio teaches mast cell degranulation can contribute to the morbidity and mortality associated with allergic diseases and Gaudenzio teaches technical constraints have limited the spatiotemporal resolution of mast cell degranulation which has hampered analysis of the dynamics and quantitative characteristics of granule exteriorization in real time at the single-cell level. Therefore, one of ordinary skill in the art would have been motivated to combine Genoskin and Gaudenzio in a method to test and determine simultaneously the inflammatory potential and the allergic or pseudoallergic potential of a substance without having to resort to an animal model. One would have a reasonable expectation of success in combining the teachings as Genoskin teaches the method provides an ex vivo model of inflamed skin comprising mast cells which reflects more precisely and reproducibly the environment of the inflamed skin as observed in vivo in a physiopathological context and Gaudenzio teaches the method for human primary mast cells in vitro can respond to distinct stimuli of activation by finely regulating the dynamics and features of mast cell granule secretion and Gaudenzio teaches the dynamic imaging system can follow in real time the spatially complex, rapidly evolving features of mast cells undergoing activation and the method can be used to determine mast cell activation in vivo with intradermal injections. Solely to rebut Applicant’s arguments regarding that the Genoskin model is a psoriasis model, Balak (Balak DM, et. al. Psoriasis (Auckl). 2017 Dec 7;7:87-94) teaches exposure to certain drugs (“substance”) can elicit an induction or exacerbation of psoriasis and identifying medication-related exacerbations and induction of psoriasis can be challenging (Abstract; page 88, left col. para. 1; Table I). Thus one of ordinary skill in the art would recognize that a method for testing the inflammatory potential and allergic or pseudoallergic potential of a substance can be performed by administering a substance to a skin explant that is a model of psoriasis.
Conclusion
No claims 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.
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/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632