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 .
DETAILED ACTION
Applicant’s response filed on 08/18/2026 is duly acknowledged.
Claims 1-15 as amend/presented on 07/25/2024 are pending in this application.
Election/Restrictions
Applicant's election with traverse of Species A (directed to claims 1-11; directed to “An analysis method for analyzing heparin-dependent platelet activation in a patient…”) in the reply filed on 08/18/2026 (see REM, p. 2-7) is acknowledged. The traversal is mainly on the ground that the species A, B and C as currently claimed do not lack unity of invention as the cited prior art of “Padmanabhan does not disclose the features the three groupings share” (see REM, p. 4-5) and that “A broad and practical view of the claims confirms unity” (see REM, p.7).
However, upon further considerations, the requirement for species election as previously made by the examiner has been withdrawn, all species have been re-joined and examined on their merits in this action hereinafter.
Claims 1-15 as amend/presented have been examined on their merits in this action.
Priority
This application is a 371 of PCT/EP2023/052029 9filed on 01/27/2023), which claims foreign priority from a French application FR 2200734 filed on 01/28/2022.
Objection to Specification
The disclosure is objected to because of the following informalities: the instant disclosure as presented recites limitations “Patient Test (PT) Series” (see for instance, SPEC, p.4, line 24; Tables 3-14) as well as “Patient Test (TP) Series” (see for instance, SPEC, p. 11, line 10; p. 18, formula [Math 4]), which appears to be a reference to the same component, i.e. “Patient Test (PT) Series”. Applicant is advised to amend the specification of record to correct the situation in order to avoid ambiguity. Appropriate correction is required.
Claim Objections
1. Claim 1 (as presented) is objected to because of the following informalities: claim 1 in step 2), line 5 recites the limitation “mixture basal”, which should be amended to recite “basal mixture” (taken as typographical error). Appropriate correction is required.
In addition, claim 1 in step 3) line 1 recites “and the subsequent labeling of…”, which should be amended to recite “and the specific labeling of…” where the word “the” should be deleted. Appropriate correction is required.
2. Claims 12 and 14 (as presented) are objected to because of the following informalities: Claim 12 recites in line 3 limitations “…the method according to claim 7, as well as a step 6) of interpretation …”, which should be amended to recite “…the method according to claim 7, further comprising a step 6) of interpretation …”, in order to clarify the process as intended. Appropriate correction is required. Similar correction in instant claim 14 (in line 3) is also required.
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.
Claims 1-15 (as presented) 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.
1. Claim 1 recites the limitation "the mixture basal" in line 5 of step 2). There is insufficient antecedent basis for this limitation in the claim. Claim 1 as currently recited does not provide a reasonable basis for “a mixture basal” (taken as “a basal mixture”; see above for claim objection). Appropriate correction is required.
2. Regarding claim 1 as presented, the phrase “preferably” (taken as "for example") 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). The recitation in step 1, lines 5-6 of limitations “a monoclonal antibody specifically directed against the platelet factor 4 modified by a polyanion, preferably by heparin, or one of the fragments thereof”, is deemed indefinite as it is unclear if the limitations followed by “preferably” are in fact part of the process limitations as claimed, or just an example thereof. Appropriate correction is required.
Similarly, claim 3 recites the term “preferably two mixtures…” in line 2, and in addition in lines 4 and 5 (for instance “preferably between 0.02 and 0.08 IU/ml” in line 4), which render the claimed process indefinite because of the same reasons as discussed above. Appropriate correction is required.
Similar issues (regarding the phrase “preferably”) pertain to instant claims 8, 10 and 11, as currently presented, which render claimed processes indefinite for the same reasons of record as discussed above, and appropriate correction is required.
3. Claim 1 recites the limitations in method steps 1) and 2) at various places requiring “mixing a sample of whole blood from the patient…”, or “at least one mixture of a sample of whole blood from the patient…”, which is ambiguous and confusing. It is not clear if it is the same “sample of whole blood” that is obtain from the patient “suspected of having thrombocytopenia…” (i.e. taken at one time point), or there are many samples of whole blood from the same patient taken at different time points, for instance. In addition, the recitation “at least one mixture of a sample of whole blood from the patient…” is also ambiguous as it is unclear as to what exactly is encompassed by the step as presented. Are there multiple mixtures that are pre-made, or for that matter other mixtures that may have different components being mixed, out of which there is only one mixture that has been recited ? As presented, the metes and bounds of the claimed process does not appear to be properly defined. Since, none of the dependent claims clarify this point, they are also rejected as being indefinite for the same reasons of record. Appropriate correction and/or explanation is required.
4. Claim 1 in step 2), lines 6-7 recites the limitations “with PF4 to obtain a mixture 2a”, which is ambiguous and confusing because it is unclear if the “PF4” used in the instant step is the same as the “exogenous platelet factor (PF4)” recited in step 1) (see lines 5, 9 and 13), or it uses yet another “PF4”. The metes and bounds of the claimed process does not appear to be properly defined. Similar situation is pertinent in step 2), lines 9 and 12. Appropriate correction is required.
5. Claim 1 in step 2) line 3 recites the limitation of “a Strong agonist”, which is taken as a relative or comparative term, and it’s not clear as to what exactly is being encompassed and/or referred to, and in what terms- in terms of degree, or strength, or activation, or any other mechanistic details not yet recited in the claim(s). It is also not clear if “a platelet activator” of any kind would be considered as a “strong agonist” per se. The disclosure of record does not provide for any specific guidance and/or measure as to how one would relate to the required limitation as presented in the process as claimed (see instant SPEC, p. 11, last paragraph, for instance). Since, none of the dependent claims remedy this situation, they are also rejected as being indefinite for the same reasons as discussed above. Appropriate correction is required.
6. Claim 5 recites the limitations “low concentrations of heparin” and “high concentrations of heparin” (see lines 5-6). There is insufficient antecedent basis for these limitations in the claim. Claim 5 directly depends from claim 4, which in turn depends from independent claim 1 that do not appear to provide a basis for such relative limitations of “low” and “high” concentrations of heparin per se. Applicants are advised to amend claim 5 such that it recites the respective concentration ranges already provided in the independent claim 1, step 1), instead.
Similar situation arises in dependent claim 13 (lines 2-3) and claim 15 (lines 3-4), which should also be amended appropriately. Appropriate correction is required.
7. Claim 1 in step 4) recites the limitations “the analysis of all mixtures…”. There is insufficient antecedent basis for this limitation in the claim. Claim 1 as presented does not provide reasonable basis for the limitation of “an analysis of all mixtures..” per se. Also, it is unclear as to what kind of analysis is being encompassed by the claimed process as presented. It is noted that the dependent claim 6 recites the limitations “(T)he method according to claim 1 which is a flow cytometry analysis method”. However, claim 1 does not require any such analytical means or technique for such limitation for step 4), as currently presented. Although, a broad recitation of a limitation is not deemed indefinite per se, however, since the claim requires the method step 3) which does not specifically define as to what exact kind of “labeling of the platelet population…” is being performed, an artisan of ordinary skill in the art would not reasonably contemplate and/or understand the metes and bounds of the claimed process with the generic method step 4), as currently recited. Appropriate correction is required.
8. Claim 1, in step 3), line 1 recites the limitations “the VS and TP series”. There is insufficient antecedent basis for this limitation in the claim. Claim 1 in step 2), line 1 recites the limitations “the preparation of a Patient Test (PT) series…”. However, there is no pertinent reference to “a TP series” per se. It is not clear if it is the same as “Patient Test (PT) series” recited in step 2), or it is yet unrecited limitation of the process as claimed. The disclosure of record recites both “PT series” and “TP series” as several places, and it is not clear if they are the same or different limitations (see instant SPEC, p. 2, line 24; p. 11, lines 10 and 14; Table 3; p. 25, line 35, formula “[Math 4]” on p. 26; p. 34, line17, for instances). Appropriate correction/explanation is required. It is noted that instant claims 7 and 12-15 also recite the limitations of “TP series”, which should be appropriately corrected.
In addition, the specification of record should also be corrected to appropriately reflect the correct limitation.
For the purposes of this office action, the limitations “TP series” has been taken as referring to “Patient Test (PT)” series, i.e. PT series (as per SPEC, p. 5, lines 10-12).
Claim Rejections - 35 USC § 112 – WD Rejection
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 1-8 and 10-15 (as presented) 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 entire scope of the invention as claimed.
Claims 1, 12 and 14 as presented have been reproduced herein as follows:
“1. (Original) An analysis method for analyzing heparin-dependent platelet activation in a patient suspected of having thrombocytopenia induced by polyanion-modified antiplatelet factor 4 (PF4) antibodies, comprising the following steps:
1) the preparation of a series of tests necessary for validation and standardization, hereinafter referred to as the Validation/Standardization series (VS), said Validation/Standardization series comprising:
- mixing a sample of whole blood from the patient, diluted in an acceptable buffer, in the presence of exogenous platelet factor (PF4 ), and a monoclonal antibody specifically directed against the platelet factor 4 modified by a polyanion, preferably by heparin, or one of the fragments thereof, in order to obtain a mixture 1a;
- at least one mixture of a sample of whole blood from said patient, diluted in an acceptable buffer, with exogenous PF4, a monoclonal antibody specifically directed against polyanion-modified PF4, or a fragment thereof, and heparin in a concentration comprised between 0.01 and 1 IU/ml, in order to obtain at least one mixture 1b;
- at least one mixture of a sample of whole blood from said patient, diluted in an acceptable buffer, with exogenous PF4, a monoclonal antibody specifically directed against polyanion-modified PF4, or a fragment thereof, and heparin in a concentration comprised between 10 and 200 IU/ml, in order to obtain at least one mixture 1c;
2) the preparation of a Patient Test (PT) series, said Patient Test series comprising:
- mixing a sample of whole blood from said patient, diluted in an acceptable buffer, with a platelet activator or a strong agonist, to obtain a mixture Ago;
- mixing a sample of whole blood from said patient, diluted in an acceptable buffer, to obtain the mixture Basal;
- mixing a sample of whole blood from said patient, diluted in an acceptable buffer, with PF4 to obtain a mixture 2a;
- at least one mixing of a sample of whole blood from said patient, diluted in an acceptable buffer, with PF4 and heparin at a concentration equal to the concentration used for mixture 1 b, in order to obtain a mixture 2b;
- at least one mixing of a sample of whole blood from said patient, diluted in an acceptable buffer, with PF4 and heparin at a concentration equal to the concentration used for mixture le, in order to obtain a mixture 2c;
3) the incubation of all mixtures of the VS and TP series and the subsequent labeling of the platelet population and the specific labeling of activated platelets in said population in each mixture; and
4) the analysis of all mixtures obtained in step 3).” See also 112b rejections as discussed above.
“12. (Currently Amended) A method of diagnosis of the exclusion of heparin-induced thrombocytopenia (HIT) in a patient, comprising the method according to claim 7, as well as a step 6) of interpretation of the calculated antibody-dependent platelet activation (APA) rates in each mixture of the TP series for the diagnosis of HIT exclusion.”
“14. (Currently Amended) A method of confirmation of a diagnosis of HIT in a patient suspected of having the illness, comprising the method according to claim 7, as well as a step 6) of interpretation of the calculated antibody-dependent platelet activation (APA) rates in each mixture of the TP series for the diagnosis of HIT.”
See also limitations of dependent claims 2-8, 10, 11, 13 and 15, as currently presented.
At the outset, it is to be noted that the monoclonal antibody specifically directed against polyanion-modified PF4 comprising SEQ ID NOs: 1 and 2 (instant claim 9), appear to be free of prior art and/or written description issues. However, instant claim 1 (and claims dependent therefrom) is not limited to said monoclonal antibody per se as discussed below:
The claimed process as presented by applicants on record requires “a monoclonal antibody specifically directed against the platelet factor 4 modified by a polyanion, preferably by heparin, or one of the fragments thereof” (see entire step 1 of claim 1) in order to obtain mixtures 1a, 1b and 1c, wherein the process is not limited to any specific monoclonal antibody. However, it is to be noted that the disclosure of record only relates to a monoclonal antibody specifically directed against the platelet factor 4 modified by heparin (not any polyanion), designated as “5B9” (see SPEC, p. 10-11; and cited reference to Kizlik-Masson et al, 2017; see disclosure in the attached NPL on PTO 892 form attached herewith), a humanized antibody that comprises the VH and VL sequences encoded by the SEQ ID NOs: 2 and 1, respectively, and that mimics heparin-induced thrombocytopenia (HIT) antibodies in human patients. Applicant’s disclosure and the process for analyzing heparin-dependent platelet activation in a patient suspected of having thrombocytopenia induced by heparin-modified antiplatelet factor 4 (PF4) antibodies, as shown in the results provided in Tables 3-18 for tested patients using VS and PT series data, are relevant only with reference to the specific 5B9 humanized monoclonal antibody employed in the assay, and not with any other antibody that does not have the same specific binding and/or functional properties. In addition, applicants have provided no evidence or comparative data on record that compares with other known monoclonal antibodies in prior art, such as KKO, a murine IgG2b HIT antibody that is also specific for detecting HIT (see for instance, Kizlik-Masson et al, p. 2072, “Discussion”, 2nd full paragraph), but may have distinct binding profile and effects that result in functionally different outcomes (for example, there are significant binding/activation differences based on specificity of binding to PF4/H complexes and PF4 itself; see Kizlik-Masson et al, p. 2072, “Discussion”, 2nd full paragraph, and cited reference of Asada et al- wherein the antibody bound PF4/H complex and PF4 alone similarly and induced platelet activation, even without heparin). However, given the variability in terms of type of monoclonal antibody and their variable functional properties known in the prior art, the disclosure of record does not provide adequate guidance and/or comparative data as to how the analysis process for “heparin-dependent platelet activation” in a patient suspected of having thrombocytopenia induced by heparin-modified antiplatelet factor 4 (PF4) antibodies, as claimed can be successfully performed using any type of monoclonal antibody, as currently claimed. Also, since the dependent claims 12 and 14 (that are directed to further interpretation of the analyses data, i.e. confirmation, or exclusion from HIT), ultimately are based on the calculations for “antibody-dependent platelet activation (APA)” levels and/or rates obtained from the “mixtures Ago, 2a, 2b, and 2c of the TP series” (see instant claims 4 and 7 as presented), it should be clear that not any or all monoclonal antibodies (directed against the PF4 modified by any polyanion, or heparin for that matter) would be found suitable for such diagnostic interpretation as required by the claims.
Thus, it appears from the above discussion that at the time the application was filed applicants are not in possession of the entire scope of the invention as claimed.
Appropriate correction is required.
Conclusion
NO claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SATYENDRA K. SINGH whose telephone number is (571)272-8790. The examiner can normally be reached M-F 8:00- 5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, LOUISE W HUMPHREY can be reached at 571-272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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SATYENDRA K. SINGH
Primary Examiner
Art Unit 1657
/SATYENDRA K SINGH/Primary Examiner, Art Unit 1657
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