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 .
Claims 1, 3, 5-6, 9, and 11-12 are currently amended.
Claims 4, 7-8, and 13 are cancelled.
Claims 1-3, 5-6, and 9-12 are pending and under examination on the merits.
Priority
Applicant’s claim of priority to CN 202210375754 A, filed 04/11/2022, is acknowledged. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawn Objections/Rejections
The objections to the specification are withdrawn in light of the corrective amendments to the specification dated 01/07/2026. Any and all objections and rejections of claims 4, 7-8, and 13 are withdrawn as moot in light of the 01/07/2026 claim amendments which cancel claims 4, 7-8, and 13. The objections to claim 1 and 9 are withdrawn as addressed in light of the corrective claim amendments dated 01/07/2026. The rejections of claims 3, 6, and 12 under 35 USC §101 are withdrawn as addressed by the corrective claim amendments dated 01/07/2026. The rejections of claims 3, 6, 12 under 35 USC 112(b) are withdrawn as addressed by the corrective claim amendments dated 01/07/2026. The rejection of claims 9 and 11 under 35 USC 112(b) are withdrawn as addressed by the clarifying and persuasive arguments presented in of the remarks dated 01/07/2026 and Applicant’s acceptance of the Examiner’s claim interpretation (see for example, pages 18-21). The enablement rejection is withdrawn in good faith reliance on Applicant’s statement that the Examiner had misunderstood what Applicant intended to claim (see for example, page 16 of the 01/07/2026 remarks) where the Examiner understands this argument, in light of the amendments, to encompass the use of the ‘other antibodies’ after the recited gating combinations using lactoferrin and lysozyme and subsequently using CD45 expression (see for example, the claim interpretation section, newly added below). The rejections of the claims under 35 USC §103 are withdrawn in light of the claim amendments dated 01/07/2026.
New-Claim Interpretation
Recitations of ‘medium strength expression’ (as in claim 1 in line 6 for example) are being interpreted to read ‘ a medium strength lactoferrin expression/lysozyme+ cell subset’ in light of the surrounding claim language.
Recitations of a/the “lactoferrin+” cell subset, “medium-strength lactoferrin expression, lysozyme+” subset, and cell subsets “with low expression of lactoferrin and lysozyme” are being interpreted to correspond to the then recited subsets of: ‘the lactoferrin+ and lysozyme+ being a mature granulocyte subset’, ‘’medium-strength lactoferrin expression and the lysozyme+ cell subset being a monocyte subset (understood to represent a single subset of cells)’, ‘low expression of lactoferrin and lysozyme being other cell subsets. This appears to be consistent with what is described and enabled in the instant disclosure, particularly in accordance with: the lactoferrin+ and lysozyme+ cell sets are mature granulocyte subsets, expressing mature granulocyte markers CD33, CD11b, and CD15; with medium-strength Lactoferrin, the Lysozyme+ cell set is a monocyte subset, expressing monocyte markers CD14 and CD64; and the cell sets with low expression of Lactoferrin and Lysozyme are a nucleated red blood cell subset and a lymphocyte subset (see for example, the brief description of Fig. 1A-1I at pages 7-8 of the instant specification).
As noted in the previous office action dated 11/08/2025 and confirmed by Applicant at page 18 (part 4) of the remarks dated 01/07/2026 (and as appears consistent with the notation in pages 4-5, discussing the table, of the instant specification), the c modifying the CD3 and IgM is deemed to mean that cytoplasmic CD3 or IgM is bound.
Recitations of abnormal cells or an abnormal cell set or cells having abnormal expression of antigens is to be interpreted as follows to correspond to Applicant’s clarifying remarks dated 01/07/2026 at exemplary page 17: abnormal cells are the subset having low lactoferrin and lysozyme expression and weak CD45 expression (showing in the instant figures), lymphocytes are the subset having low lactoferrin and lysozyme expression and higher (than the weakly expressing abnormal cell subset) CD45 expression, nucleated RBCs are the subset having low lactoferrin and lysozyme expression and being CD45-negative (see for example, page 17 of the 01/07/2026 remarks citing paragraphs 0013, 0114, 0126, 0138, 0150, and 0162 (note that the instantly filed specification does not contain paragraph numbers. The Examiner, in an effort to advance prosecution, assumes and proceeds with the understanding that the paragraphs of the instant specification cited by Applicant are the paragraphs as numbered in the version of the instant disclosure published and publicly available from Google Patents, a copy of which has been appended and cited on the PTO-892 form associated with this Office Action).
Applicant, in the 01/07/2026 remarks (see for example, pages 20-21) accepts the Examiner’s interpretation the of recited primitive and juvenile cell subset is a single subset (where primitive and juvenile are synonymous terms) identical in definition to the blast cells gated and analyzed in Tsai et al (W02019108554 A1; as cited on the 02/22/2023 IDS as citation 1 under Foreign Patent Documents; as preciously cited in the office action dated 11/03/2025).
Other common hematologic tumor immunophenotyping antibodies, as recited in the instant claims, in the effort of advancing compact prosecution, are being interpreted as referring to the antibodies recited in the table of instant claim 11. Further, recitations of using these other antibodies are interpreted, to first require gating using the lysozyme and lactoferrin expression and further CD45 expression gating as is consistent with the claim drafting and the described and enabled embodiments throughout the instant disclosure (see for example, Figures 1-5M).
Step 2 of claim 12 is interpreted to be accomplished using the 43 antibodies recited in the kit of instant claim 11 from which instant claim 12 depends.
Maintained-Claim Interpretation
Where ‘other cell subsets’ is recited, this is presumed to refer to the cells gated and labeled as ‘other cells’ in the figures of the instant disclosure and/or an abnormal subset, a nucleated RBC subset, and a lymphocyte subset (see for example, pages 12 and 20-21 of the remarks dated 01/07/2026).
New-Claim Objections
Claim 1 is objected to because of the following informalities: in line 6, “lactoferrin+ cell set” should read “a lactoferrin+ cell set”. In line 6, “medium strength lactoferrin expression” should read “a medium strength lactoferrin expression/lysozyme+ cell set”. It is recommended for clarity that claim 1 be amended such that lines 8-9 read “...the lysozyme antibody wherein the lactoferrin+…,” to promote clarity for what is claimed and the connection of recited elements. Further note that the recited subsets in line 6-8 (such as the recited lactoferrin+ cell set) should be made to be consistent in terminology and plurality with all other corresponding references throughout the claims (such as in claim 1, lines 9-10 reciting the lactoferrin+ and lysozyme cell sets being a mature granulocyte subset).
Claim 3 is objected to because of the following informalities: in line 4 “a mature granularity subset, a monocyte subset, and other cell subsets” should read “4 “the mature granularity subset, the monocyte subset, and the other cell subsets” for consistency and clarity in light of the drafting of claim 1 from which claim 3 depends. In line 6, “lactoferrin+ cell set” should read “the lactoferrin+ cell set”. In line 6, “medium strength lactoferrin expression” should read “a medium strength lactoferrin expression/lysozyme+ cell set”. It is recommended for clarity that claim 3 be amended such that lines 8-9 read “...the lysozyme antibody wherein the lactoferrin+…,” to promote clarity for what is claimed and the connection of recited elements. Further note that the recited subsets in line 6-8 (such as the recited lactoferrin+ cell set) should be made to be consistent in terminology and plurality with all other corresponding references throughout the claims (such as in claim 1, lines 9-10 reciting the lactoferrin+ and lysozyme cell sets being a mature granulocyte subset). In line 17, “CD45+ cell set, CD45 weakly positive cell set, and CD45- cell set” (interpreted to mean, from the other cell subsets, the lymphocyte subset, the abnormal subset, and the nucleated RBC subset, respectively) should be amended to recite “a CD45+ cell set, a CD45 weakly positive cell set, and a CD45- cell set”.
Claim 6 is objected to because of the following informalities: in line 4 “a mature granularity subset, a monocyte subset, and other cell subsets” should read “the mature granularity subset, the monocyte subset, and the other cell subsets” for consistency and clarity in light of the drafting of claim 1 from which claim 6 depends. In line 6, “lactoferrin+ cell set” should read “the lactoferrin+ cell set”. In line 6, “medium strength lactoferrin expression” should read “a medium strength lactoferrin expression/lysozyme+ cell set”. It is recommended for clarity that claim 6 be amended such that line 8 reads “...the lysozyme antibody wherein the lactoferrin+…,” to promote clarity for what is claimed and the connection of recited elements. Further note that the recited subsets in line 6-8 (such as the recited lactoferrin+ cell set) should be made to be consistent in terminology and plurality with all other corresponding references throughout the claims (such as in claim 1, lines 9-10 reciting the lactoferrin+ and lysozyme cell sets being a mature granulocyte subset).
Claim 9 is objected to because of the following informalities: in line 5, “lactoferrin+ cell set” should read “a lactoferrin+ cell set”. In line 5, “medium strength lactoferrin expression” should read “a medium strength lactoferrin expression/lysozyme+ cell set”. It is recommended for clarity that claim 9 be amended such that lines 7 read “...the lysozyme antibody wherein the lactoferrin+…,” to promote clarity for what is claimed and the connection of recited elements. Further note that the recited subsets in lines 5-10 (such as the recited lactoferrin+ cell set) should be made to be consistent in terminology and plurality with all other corresponding references throughout the claims (such as in claim 9, lines 7-8 reciting the lactoferrin+ and lysozyme cell sets being a mature granulocyte subset).
Claim 11 is objected to because of the following informalities: in line 5, “lactoferrin+ cell set” should read “a lactoferrin+ cell set”. In line 5, “medium strength lactoferrin expression” should read “a medium strength lactoferrin expression/lysozyme+ cell set”. It is recommended for clarity that claim 11 be amended such that lines 7 read “...the lysozyme antibody wherein the lactoferrin+…,” to promote clarity for what is claimed and the connection of recited elements. Further note that the recited subsets in lines 5-10 (such as the recited lactoferrin+ cell set) should be made to be consistent in terminology and plurality with all other corresponding references throughout the claims (such as in claim 11, lines 7-8 reciting the lactoferrin+ and lysozyme cell sets being a mature granulocyte subset).
In light of the drafting of claim 11 and the dependence of claim 12 from claim 11, it is noted that “a mature granulocyte subset, a monocyte subset and other cell subsets” in line 11 should read “the mature granulocyte subset, the monocyte subset, and the other cell subsets”. Further, “lactoferrin+ cell set, medium-strength lactoferrin expression, lysozyme+ cell set, and cell sets with low expression of lactoferrin and lysozyme” in lines 13-14 should read “the lactoferrin+ cell set, the medium-strength lactoferrin expression/ lysozyme+ cell set, and cell sets with low expression of lactoferrin and lysozyme”. Furthermore, “by the lactoferrin antibody and the lysozyme antibody, the lactoferrin+ and lysozyme+ cell sets” as recited in lines 15-16 should read “by the lactoferrin antibody and the lysozyme antibody, wherein the lactoferrin+ and lysozyme+ cell sets”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Maintained-35 USC § 112(a)
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.
Written Description
Claims 1-3, 5-6, and 9-12 are rejected, with new grounds for rejection necessitated by amendments made to claim 3 in the claim amendments dated 01/07/2026, 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.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B. V. v. Dianwnd Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The Application claims a broad genus of antibodies and gating combinations thereof without disclosure of a conserved structure/representative number of species to adequately describe said genera. The Application discloses only 1 clone for each antibody recited which has been shown to function in the claimed methods of immunophenotyping and only discloses the limited gating combinations shown in figures 1-5M . Therefore, in view of this disclosure, Applicant is claiming a broad genus of antibodies and gating combinations thereof without a representative number of species of said genera. The specification does not provide adequate written description for the entire claimed genera of species of antibodies or combinations thereof as claimed, because in the absence of empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically, which light and heavy chain CDR sequence combinations (bearing any mutations or not) might be included in the genera so as to function for mass cytometric/immunophenotypic analysis as claimed.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Applicant has only fully disclosed 1 clone per antibody and a limited number of gating combinations. Thus, given the substantial antibody structure variation within the genus as well as the high level of unpredictability in the art, the disclosure of only 1 clone per antigen/antibody and the limited disclosure of gating combinations shown in figures 1-5M is not sufficiently representative of the entire genera claimed (encompassing CDRs not described or even invented and/or multiple combinations which may not have been discovered for said immunophenotypic analysis).
Furthermore, Applicant has not disclosed relevant, identifying characteristics of CDR region amino acid sequences that confer upon an antibody the ability to function as claimed in the immunophenotypic method and/or to function as claimed in combination with the antibodies as instantly recited because the instant specification does not provide structural antibody features that correlate with a capacity to function in the claimed methods and/or combinations.
Absent a clear description of the at least minimal structural features correlating with a capacity to function as claimed which are shared by members of a genus commonly sharing this function, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which heavy and light chain CDR amino acid sequences may be combined and used such that the resultant heavy and light chain variable regions comprise six CDRs that confer the ability to function as claimed.
Furthermore, while the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. For example, Al Qaraghuli et al (2020, Nature Scientific Reports 10:13969), state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen. This suggests that a change in the CDR sequence may result in a conformationally different paratope which may fail to bind target as claimed. Here, it is unclear what CDRs will bind an epitope allowing for use in the claimed method(s) or for combination with the other antibodies to identify/distinguish the recited cell subsets. Rabia, et al (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Tiller et al (2017, J. Biol. Chem. (2017) 292(40) 16638–16652) and Tsuji et al (2022, J Virol 96:e00071-22) teach that mutations in the CDRs (especially HCDR3 are unpredictable and accompanied by tradeoffs in performance (for example increased affinity may lead to decreased specificity); see references in their entirety paying particular attention to the abstract of Tiller et al and the abstract and results section of Tsuji et al). The above cited references underscore the unpredictability of even a single mutation in the CDRs. The instant claims allow for any generic antibody binding the recited targets, in multiple, unsupported combinations for immunophenotypic analysis to distinguish various, vaguely defined cell subsets.
Accordingly, absent empirical determination, one skilled in the art would be unable to predict or envision which CDR sequences comprised within the genus would possess the binding traits needed to function as claimed and which antibodies may be combined such that the resultant combination possesses antigen-binding qualities capable functioning as claimed. The general knowledge and level of skill in the art does not adequately supplement the omitted description, because specific, not general guidance is needed. Since the disclosure fails to describe relevant, identifying structural characteristics, in the form of fixed heavy and light chain CDR amino acid sequence combinations, that correlate with the ability to function as claimed, and because the one disclosed clone/species detailed above is not sufficient to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met. Further, the limited gating strategies disclosed in figures 1-5M similarly are not deemed to be representative of the breadth of gating combinations encompassed by the claims.
The claims require the use of multiple antibodies claimed by the antigen which the bind for use in an immunophenotypic method. The specification does not describe which amino acid residues of the antibody are responsible for the functions claimed. Rather, the specification implies that these antibodies must first be screened to ascertain if they have the functions required by the instant claims. Although the specification provides disclosure of 1 clone per antigen/antibody recited and the combinations shown in figures 1-5M, it fails to disclose the structures common to all members of the genus of antibodies encompassed by the broad recitation provided by applicant. The specification does not disclose the structure of all of the claimed antibodies and fails to disclose which sequences are responsible for the functions claimed. The specification further fails to describe which antibody structures are required to identify the related subgroups recited. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genera of antibodies and combinations thereof that would function in the method(s) as claimed, but rather has presented the public with an idea of how to perform an assay that might identify some peptides that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
In Ariad, the court further noted that the written description plays a particularly important role in the biological arts, where patentees might otherwise be tempted to claim a genus of compounds by its function or result:
“The written description requirement also ensures that when a patent claims a genus by its function or result, the specification recites sufficient materials to accomplish that function—a problem that is particularly acute in the biological arts. 5 See Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, 1, “Written Description” Requirement, 66 Fed. Reg. 1099, 1105-1106 (Jan. 5, 2001). This situation arose not only in Eli Lilly but again in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 [69 USPQ2d 1886] (Fed. Cir. 2004). In Rochester, we held invalid claims directed to a method of selectively inhibiting the COX-2 enzyme by administering a non-steroidal compound that selectively inhibits the COX-2 enzyme. Id. at 918. We reasoned that because the specification did not describe any specific compound capable of performing the claimed method and the skilled artisan would not be able to identify any such compound based on the specification's function description, the specification did not provide an adequate written description of the claimed invention. Id. at 927-28. Such claims merely recite a description of the problem to be solved while claiming all solutions to it and, as in Eli Lilly and Ariad's claims, cover any compound later actually invented and determined to fall within the claim's functional boundaries—leaving it to the pharmaceutical industry to complete an unfinished invention.”
Ariad Pharmaceuticals., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc). Emphasis added.
The Federal Circuit has clarified written description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies in the present claims.
Although screening techniques can be used to isolate CDR variant antibodies that possess the ability to function as claimed, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the 'written description' requirement is broader than to merely explain how to 'make and use'; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.”
Claim 3, in newly added step 3 requires “analyzing expression of antigens of related subsets by other common hematologic tumor immunophenotyping antibodies to determine whether there is abnormal expression of the antigens of related subsets”. The instant specification provides no clear description enabling the artisan to readily envisage the species encompassed by the recited genus of related subsets which may be predictably isolated and analyzed in the claimed method(s).
Thereby, the antibodies, and combinations thereof for distinguishing the recited cell subsets, as claimed are only disclosed by function/insufficient structure, without a representative number of species or unifying, conserved structure clearly enabling one skilled in the art to readily envisage the members of the genus claimed which would function as claimed in the claimed method(s). Therefore, the claims are deemed to fail to meet the written description requirement, as presently drafted.
New-35 USC § 112(b)
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 1-3, 5-6, 9, and 11-12 are newly rejected, as necessitated by the claim amendments dated 01/07/2026, 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.
Claim 1 appears to use inconsistent terminology and plurality to recite particular cell subsets. For example, claim 1 in line 6 recites “lactoferrin+ cell set” which, in light of the instant disclosure in its totality, appears to correspond to the subsequent recitation in lines 8-9 of “the lactoferrin+ and lysozyme+ cell sets”. The description of the cell set has shifted from singular to plural (which is further complicated by the further recitation that the “lactoferrin+ and lysozyme+ cell sets [are] a mature granulocyte subset” where a the subset(s) shifts again to become singular). This apparent subset is effectively given 3 different descriptors, which in a case reciting the subsets by their biomarker expression is of profound significance to the metes and bounds of the claims. While one example is provided and described, this issue is repeated for other subsets and pervades the entirety of the claim set. This inconsistent claim drafting creates ambiguity as to what is claimed because it requires the artisan to interpret what recitations encompass one another and to argue as to what Applicant intends to claim and seeks to defend from infringement. The claims should, at the very least, recite each subset Applicant wishes to include/require as having a single and clear biomarker expression pattern that permits the artisan to readily distinguish each claimed subset from the claim recitation (noting that where multiple cell subsets are, for example, lactoferrin +, no single subset should be described solely as lactoferrin+ and that relative terminology (such as ‘medium strength expression’) should be clarified or avoided). Each subset should be described individually and numerosity (single or plural status) should be clear and maintained throughout the recitation. Therefore, the claim is rejected where the metes and bounds of the claim are indefinite.
Claim 2 depends from claim 1 and incorporates, without remedy, the above noted deficiency. Therefore, claim 2 is included in this rejection.
The term “lactoferrin+” (as in lactoferrin+ cell set) in claims 1, 3, 6, 9, and 11-12 (incorporated in dependent claims 2 and 5) is a relative term which renders the claims indefinite. The term “lactoferrin+” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. There are multiple cell sets which are arguably lactoferrin+ (such as the medium strength lactoferrin expression, lysozyme+ cell set). Therefore, either the term ‘lactoferrin+’ must be more clearly defined so as to be distinguished from other cell sets or the cell sets must be more clearly described by the claim recited claim terminology (for example, would a low expression lactoferrin expression set be called lactoferrin+ and fall within the claim scope or not).
The term “medium-strength” (as in medium strength lactoferrin expression, lysozyme+ cell set) in claims 1, 3, 6, 9, and 11-12 (incorporated in dependent claims 2 and 5) is a relative term which renders the claims indefinite. The term “medium-strength” is not defined by the claim, the specification does not provide a clear and definitive standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. There are multiple cell sets which are arguably lactoferrin+/medium-strength lactoferrin expression. Artisans are left to dispute the boundaries of what constitutes a ‘medium-strength’ lactoferrin expression. Therefore, either the term ‘“medium-strength”’ must be more clearly defined so as to be distinguished from other cell sets or the cell sets must be more clearly described by the claim recited claim terminology.
The term “lysozyme+” (as in medium strength lactoferrin expression, lysozyme+ cell set) in claims 1, 3, 6, 9, and 11-12 (incorporated in dependent claims 2 and 5) is a relative term which renders the claims indefinite. The term “lysozyme+” is not defined by the claim, the specification does not provide a clear and definitive standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. There are multiple cell sets which are arguably lysozyme+ (such as the medium strength lactoferrin expression, lysozyme+ cell set). Therefore, either the term “lysozyme+” must be more clearly defined so as to be distinguished from other cell sets or the cell sets (such as by writing the biomarker combination in clear terms for each cell set) must be more clearly described by the claim recited claim terminology.
The term “low-expression” (as in low expression of lactoferrin and lysozyme) in claims 1, 3, 6, 9, and 11-12 (incorporated in dependent claims 2 and 5) is a relative term which renders the claims indefinite. The term “low-expression” is not defined by the claim, the specification does not provide a clear and definitive standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Artisans are left to dispute the boundaries of what constitutes a ‘low expression’. Therefore, either the term “low expression” must be more clearly defined so as to be distinguished from other cell sets or the cell sets must be more clearly described by the claim recited claim terminology. Artisans are left to dispute the boundaries of what constitutes a ‘medium-strength’ lactoferrin expression.
Regarding claims 1-2 and 11, it is unclear whether the claims are directed towards a product, a method, or a mixed product and method. Claim 1, at the preamble, recites an antibody combination, but proceeds to recite steps for using and/or products resulting from use of the antibody combination. It is unclear if use of the antibody combination and/or obtaining the resulting cells subsets is intended to be required for the claim, such that the claim would appear to be a method or a mixed product method claim, or whether the steps are not intended to be required in order to infringe the claim, such that the claim would appear to be a product claim directed towards the antibody combination. Artisans are left to dispute the metes and bounds of the claim. Claim 2 incorporates by dependency and fails to remedy this deficiency. Similarly, claim 11, at the preamble, recites a kit, but proceeds to recite steps for using and/or resulting products from use of the kit. It is unclear if use of the kit and/or obtaining the resulting cell subsets is intended to be required for the claim, such that the claim would appear to be a method or a mixed product method claim, or whether the steps are not intended to be required in order to infringe the claim, such that the claim would appear to be a product claim directed towards the kit. Artisans are left to dispute the metes and bounds of the claim. Therefore, claims 1-2 and 11 are indefinite as presently drafted.
Applicant’s Arguments and Response
A. Applicant argues that the disclosure of the clones is sufficient description because the clones are commercially available and further argues that the rejections for lack of written description under 35 USC §112(a) should be withdrawn.
Response: Applicant misunderstands the rejection. The maintained rejection is directed toward the generic recitation of the antibodies in the claims. While 1 clone is disclosed (and that clone’s structure may be ascertained by the artisan), the claims are not limited to that structure/clone, but recited genera of antibodies binding the recited antigens. The genera of antibodies are rejected as undescribed as 1 clone is not reasonably deemed a representative number of species or to convey a structure function relationship which would satisfy the written description requirement for the genera of antibodies encompassed by the claims. For example, the UCTH1 antibody is not reasonably descriptive of the claimed genus of anti-human CD3 antibodies recited in the claims. The rejections are maintained at this time.
Conclusion
No claim is allowed.
The closest prior art is Tsai et al (W02019108554 A1; as cited on the 02/22/2023 IDS as citation 1 under Foreign Patent Documents; as preciously cited in the office action dated 11/03/2025) which teach methods, kits, and reagents for cellular morphology analysis comprising contacting a sample with two or more labeled binding members, where the binding members are selected from a labeled granularity marker specific binding member, a labeled maturation marker specific binding member, and a labeled leukocyte specific binding member (see for example pages 1-2 and 7-8). The labeled composition is then assayed for the presence of 25 target bound labeled binding members, e.g., to morphometrically analyze one or more cells of the cellular sample. Tsai et al teach that cancer research and treatment, in particular, depends on the identification of rare cells, such as circulating tumor cells and minimal residual disease after chemotherapy. Recently, technologies that permit the robust and reproducible detection of abnormal cells from a biological sample are becoming more prevalent (see page 1). Tsai et al further teach that flow cytometry workflow is based on decades of experience with CD45 vs. side scatter gating (see page 1 and FIG. 1A). Granules, especially within neutrophils, eosinophils, and monocytes, refract and reflect light perpendicularly, which is measured by a side scatter detector (see pages 1-2). Any convenient assay protocol may be employed, where an assay protocol employed in a given method will depend on the nature of the label to be detected. In some instances, the methods further include contacting the sample with one or more size marker reagents. The size marker reagent may be a binding member that, e.g., associates with or reacts with, e.g., specifically or non-specifically binds to, a component of a cell, where the size marker reagents include elemental metal or a metal compound, e.g., barium and the like (see page 11, for example). Tsai et al teach that a "granularity marker" is a marker present on the surface of, or inside of, a granule. The term granule refers to a secretory vesicle within a cell, e.g., a granule of a granulocyte. Known granularity markers include VAMP7, lactoferrin, and lysozyme (see for example, page 10). Tsai et al teach that the labeled specific binding members are labeled with a mass label. A mass label or mass tag refers to a moiety suitable to label an analyte for determination by mass spectrometry, where mass labels include but are not limited to heavy stable isotope labels (e.g., 15N, 13C, 2H, 18O), isotopically distinct metabolic precursors, chemical mass labels, metal labels (e.g., transition metals, noble metals, lanthanides, Sm152, Tb159, Er170, Nd146, Nd142, and the like) (see pages 15-16). Tsai et al go on to teach that the methods include the use of elemental mass spectrometry. Elemental mass spectrometry determines the elemental composition of components within a sample and quantitatively detects elements within a sample. Any suitable elemental mass spectrometry protocol known in the art may be used for the subject methods (citing US7038199; US20140299763; Sanz-Medel et al. Anal. Bioanal. Chem. 2008, 390 (1) 3-16; Calderón-Celis et al. Anal. Chem., 2016, 88 (19), pp 9699- 15 9706: Calderón-Celis et al. J. Proteomics. 2017 Jul 5; 164:33-42 as exemplary sources) (see for example page 21). Tsai et al further teach that the methods taught may include mass cytometric (also known as elemental mass spectrometry-based flow cytometry) assaying of the labeled sample. In mass cytometry, cells are labeled with binding reagents that are "mass tagged", i.e., tagged with an element or isotope having a defined mass. In these methods, the labeled particles are introduced into a mass cytometer, where they are individually atomized and ionized. The individual particles are then subjected to elemental analysis, which identifies and measures the abundance of the mass tags used. The identities and the amounts of the isotopic elements associated with each particle are then stored and analyzed. Due to the resolution of elemental analysis and the number of elemental isotopes that can be used, it is possible to simultaneously measure up to 100 or more parameters on a single particle by without experiencing spectral overlap. The general principles of mass cytometry, including methods by which single cell suspensions can be made, methods by which cells can be labeled using, e.g., mass-tagged antibodies, methods for atomizing particles and methods for performing elemental analysis on particles, as well as hardware that can be employed in mass cytometry, including flow cells, ionization chambers, reagents, mass spectrometers and computer control systems are known (citing as exemplary: Bandura et al Analytical Chemistry 2009 81 6813-6822), Tanner et al (Pure Appl. Chem 2008 80: 2627-2641), U.S. Patent No. 7,479,630, U.S. Patent No 7,135,296, and published U.S. patent application 20080046194). Where mass cytometric analysis is performed, any convenient mass cytometry system may be employed (see for example pages 21-22). Tsai et al teach that, in certain embodiments, a particular subpopulation of cells of interest may be analyzed by "gating" based on the data collected for the entire population of cells in an analyzed sample. To select an appropriate gate, the data is plotted so as to obtain the best separation of subpopulations possible. This procedure may be performed by plotting data obtained from measurement of 5 different parameters on a two dimensional dot plot. Parameters that may be employed in such methods include, but are not limited to: forward scatter, side scatter, scatterbody signals, e.g., lactoferrin, lamin A/C, lamin B, lysozyme, serpin B1 and VAMP-7, surface marker signals, e.g., CD45, and the like, etc. A subpopulation of cells is then selected (i.e., those cells within the gate) and cells that are not within the gate are excluded. Where desired, the gate may be selected by drawing a line around the desired subpopulation using a cursor on a computer screen. Only those cells within the gate are then further analyzed by plotting the other parameters for these cells, such as data obtained from additional parameters. Where desired, the above analysis may be configured to yield counts of the cells of interest in the sample. In some embodiments, practice of the methods produces a morphometric map of cells in an 15 analyzed sample. Parameters that may be employed in generating morphometric maps based on scatterbody signals include, but are not limited to: lactoferrin, lamin A/C, lamin B, lysozyme, serpin B1, VAMP-7, and the like. In some instances, e.g., where samples are analyzed by mass based protocols, a scatterbody marker is employed as a substitute for side scatter, which is not obtainable using such protocols (see for example, page 24). Tsai et al further claim and teach a method comprising contacting a sample with a labeled granularity marker and a second labeled granularity marker specific binding member, where the granularity markers may be lactoferrin and lysozyme, where antibodies against lysozyme and lactoferrin are used (see for example, pages 8 and 41-42 and claims 1 and 6-7).
Tsai et al do not teach or make obvious the instantly recited subsets (i.e.: the medium-strength lactoferrin expression, lysozyme+ set which as monocytes) identified based upon lactoferrin and lysozyme expression gating, which is deemed to be free from the prior art. The prior art fails to teach identification of the recited cell subsets using lactoferrin and lysozyme primary gating.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US20190106498A1 (note that the CN 110730789 A filing was cited as citation 4 under Foreign Patent Documents on the 02/22/2023 IDS) teaches that minimal residual disease (MRD) assessments were performed on bone marrow aspirates and/or whole blood collected at time points as specified in FIG. 5. Flow cytometry was utilized as the primary method of MRD analysis. Suitable flow cytometry markers for MRD assessment and determining AML subtype include CD16, CD13, CD34, CD117, CD11 b, CD10, HLA-DR, CD45, CD35, CD64, IREM-2, CD36, CD105, CD14, CD33, CD71, CD36, CD105, CD33, CD71, cTdT, CD56, CD7, CD19, cMPO, cLactoferrin, cLysozyme (see for example paragraph 0221 at page 16).
Davey et al (The American Journal of Surgical Pathology, December 31, 1988, Pages 703-704, Vol. 12, No. 9; cited on the 02/22/2023 IDS) is deemed relevant to the claimed subject matter.
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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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678