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 .
Election/Restrictions
Applicant’s election of group I, TIMD4, Spp1, CD68 in the reply filed on 8/12/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 8-9, 11-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/14/2025.
Priority
The application was filed 01/31/2023 and is a national stage entry of PCT/SG2021/050458 with an international filing date: 08/04/2021, which claims foreign priority to SG10202007446W, filed 08/04/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1/31/2023 and 10/24/2025 is being considered by the examiner.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted for example figure 2 is indicated a green or red. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claims 1-7 are objected to because of the following informalities:
Claim 1 is objected to as it recites “Folr2, Serpina3i, Nid2, Slc27a6, Sema6a, Cdhl3, Bcl6b, C6, Klfl5, Marco, Cd209d, Tshz3, Bmprla, Tln2, Coro2b, Ackr2, 1110046J04Rik, Pcdhac2, Gm2253, Vsig4, Phactrl, Nprl, Cpne8, Angptl7, Gm26714, Auts2, Cxcll3, Sgce, 2900052N01Rik, Cd209b, Timd4, Cd209g, Mrcl (CD206), Sppl,I122ra2, Gm24112, Gm23010, Ighv7-1, Gm23628, Gm24620, Gm23058, Arhgef37, Gadl-ps, Gm26397, Ighv2-5, Chil3, Mir1934, 1810012K08Rik, Ighvl-59, Gm14119, Gm19620 and Snord71” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Claim 2 is objected to as it recites “CD64, MerTK, Adgrel, CD11b, CD45, CD68, and CD 163” but does not recite the full terminology for the acronym (or abbreviation). Claims are more concise when the first time an acronym (or abbreviation) is presented the full terminology is also presented. Finally an acronym (or abbreviation) may have alternative meanings to an artisan.
Appropriate correction is required.
Improper Markush Group
Claims 1-7 are rejected under the judicially approved ‘‘improper Markush grouping’’ doctrine. (See Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, page 7166). This rejection is appropriate when the claim contains an improper grouping of alternatively useable species. See In re Harnisch, 631 F.2d 716, 719–20 (CCPA 1980). A Markush claim contains an ‘‘improper Markush grouping’’ if: (1) the species of the Markush group do not share a ‘‘single structural similarity,’’ or (2) the species do not share a common use. Members of a Markush group share a ‘‘single structural similarity’’ when they belong to the same recognized physical or chemical class or to the same art-recognized class. However, when the Markush group occurs in a claim reciting a process or a combination (not a single compound), it is sufficient if the members of the group are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of them possess this property. See MPEP § 803.02.
Here each species is considered to be genes which characterizes the macrophage as being an embryonic-derived macrophage, a long-lived tissue resident macrophage, and/or a monocyte-derived macrophage
The recited alternative species in the groups set forth here do not share a single structural similarity, as each method relies on detection of different gene. Each gene that could be detected is itself located in a separate region of the genome and has its own structure. The nature of genes is that they are expressed differently in different cells. The biomarkers recited in the instant claims, and the methods which detect them, do not share a single structural similarity since each consists of a different nucleotide sequences that occurs at a different location on human genome. The only structural similarity present is that all detected genes are part of nucleic acid molecules. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated characterizes the macrophage as being an embryonic-derived macrophage, a long-lived tissue resident macrophage, and/or a monocyte-derived macrophage. The association between the claimed genes is not considered as ‘property’ as the association is a statistical construct, it is a conclusion based on analysis of a specific population and may not be present in subject outside of the population assayed. Further there is no evidence the association was known in the prior art. While the instant specification asserts genes. have a common function of being correlated with the asserted phenotype, the association between the claimed gene is not clear from their very nature. If the instantly claimed genes are placed in a group with an equal number of genes the skilled artisan could not differentiate those associated with a phenotype from those that are not associated with a phenotype. Thus the one of skill in the art could not identify those genes that are asserted to be associated with the phenotype by their very nature. Thus the instant claims have not met the requirements of a proper Markush group.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
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 1-7 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.
Claim 1 is indefinite because it lacks a positive active step relating back to the preamble. The preamble recites a method of characterising a macrophage in a tissue of a subject, however the last positive active step is drawn to determining an expression of one or more biomarkers in the macrophage, wherein the one or more biomarkers. Therefore it is unclear as to whether the method is drawn to characterising a macrophage in a tissue of a subject or determining an expression of one or more biomarkers in the macrophage, wherein the one or more biomarkers.
Claim 1 has been amended to recite, “the method characterises the macrophage as being an embryonic-derived macrophage, a long-lived tissue resident macrophage, and/or a monocyte-derived macrophage..” The metes and bounds of this are unclear as the claim provides no nexus of how determining expression of the claimed markers provides for this characterizing. Thus the claims appears to be vague, unclear and incomplete how characterizing the macrophage as being an embryonic-derived macrophage, a long-lived tissue resident macrophage, and/or a monocyte-derived macrophage is done.
Claim 3 recites, “wherein the method further comprises determining the characteristics of the cells using t- SNE (T-distributed Stochastic Neighbour Embedding (t-SNE)) and/or UMAP algorithm (Uniform Manifold Approximation and Projection).” The recitation of “the characterisitics” may be attempting to find antecedent basis in the wherein clause of claim 1. However the claim is vague, unclear and incomplete how t-SNE or UMAP are used to characterise the macrophage as being an embryonic-derived macrophage, a long-lived tissue resident macrophage, and/or a monocyte-derived macrophage.
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.
Claim 4 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. Claim 1 has been amended to recite, “wherein the method characterises the macrophage as being an embryonic-derived macrophage, a long-lived tissue resident macrophage, and/or a monocyte-derived macrophage. This was previously a limitation present in claim 4. Thus claim 4 appears to be broader than claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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.
Claims 1-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation and mental step without significantly more. The claim(s) recite(s) the abstract idea or mental step of det3ermining gene expression which broadly encompasses examining data from a microarray or whole exosome sequencing experience.. Further the claim has been amended to recite, “the method characterises the macrophage as being an embryonic-derived macrophage, a long-lived tissue resident macrophage, and/or a monocyte-derived macrophage “ which is a natural law or correlation. This judicial exception is not integrated into a practical application because if there is no additional steps depend from or otherwise integrate the judicial exception. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims require no specific reagents.
Claim analysis
The instant claim 1 is directed towards a method of characterising a macrophage in a tissue of a subject, the method comprising;determining an expression of one or more biomarkers in the macrophage, wherein the one or more biomarkers is selected from the group consisting of Folr2, Serpina3i, Nid2, Slc27a6, Sema6a, Cdhl3, Bcl6b, C6, Klfl5, Marco, Cd209d, Tshz3, Bmprla, Tln2, Coro2b, Ackr2, 1110046J04Rik, Pcdhac2, Gm2253, Vsig4, Phactrl, Nprl, Cpne8, Angptl7, Gm26714, Auts2, Cxcll3, Sgce, 2900052N01Rik, Cd209b, Timd4, Cd209g, Mrcl (CD206), Sppl,I122ra2, Gm24112, Gm23010, Ighv7-1, Gm23628, Gm24620, Gm23058, Arhgef37, Gadl-ps, Gm26397, Ighv2-5, Chil3, Mir1934, 1810012K08Rik, Ighvl-59, Gm14119, Gm19620 and Snord71,wherein the method characterises the macrophage as being an embryonic-derived macrophage, a long-lived tissue resident macrophage, and/or a monocyte-derived macrophage.. The correlation in the wherein clause in a natural correlation or phenomena. The determining step broadly encompasses reading a report from microarray experiment or whole exosome sequencing and thus could be considered a mental step or abstract idea.
The determining expression of a biomarker as indicated above can be considered a mental step. Alternatively if can be considered an active step.
Dependent claims set forth further limitations to selecting cells, how to characterize cells and gne expression..
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea and law of nature or natural phenomena.
With regards to claim 1, the claim recites, “determining an expression of one or more biomarkers in the macrophage,.” The determining step broadly encompasses reading a report from microarray experiment or whole exosome sequencing and thus could be considered a mental step or abstract idea).
Further claim 2 recites, “wherein the method characterises the macrophage as being an embryonic-derived macrophage, a long-lived tissue resident macrophage, and/or a monocyte-derived macrophage.” This is a natural correlation.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as the claims provide no steps which depend from or otherwise integrate the judicial exception. .
Step 2B. Does the claim recite additional elements that are significantly more then the judicial exceptions? No
With regards to claim 1 recites determining biomarker expression which broadly encompasses reading a report. If the determining gene expression is considered an active step, it is routine and conventional in view of the teachings of Dick (Nature Immunology | VOL 20 | JANUARY 2019 | 29–39), Mass (Science mag (2016) volume 353, pages 1114) and Liu (CELL, vol. 178, no. 6, 5 September 2019)
Thus the claim does not provide additional steps which are significantly more.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-7 are is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dick (Nature Immunology | VOL 20 | JANUARY 2019 | 29–39).
As noted in the MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” Further, a preamble is generally not accorded any patentable weight where it merely recites the purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process steps or structural limitations are able to stand alone. See In re Hirao, 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951). Accordingly, the claim language of "a method of characterising a macrophage in a tissue of a subject” merely sets forth the intended use or purpose of the claimed methods, but does not limit the scope of the claims.
MPEP 2111 states: Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. However, examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are:
(A) “adapted to” or “adapted for” clauses;
(B) “wherein” clauses; and
(C) “whereby” clauses.
The determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina, 283 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a “wherein” clause limited a process claim where the clause gave “meaning and purpose to the manipulative steps”). In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a “‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention.” Id. However, the court noted (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id.
Thus the broadest reasonable interpretation is the claims require detection of the recited biomarkers.
With regards to claim 1, Dick teaches isolation of macrophages were isolated and gene expression was determined (methods (tissue isolation and transcriptional array). Dick teaches, “Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate mapping” (abstract). Dick teaches, “After myocardial infarction, the phosphatidylserine receptor TIMD4 and CCR2 emerged as mutually exclusive markers of resident macrophages and recruited macrophages, respectively. Resident macrophage abundance within the infarct zone was markedly reduced after infarction and slowly increased through in situ proliferation. Depletion of diphtheria toxin receptor–labeled resident (Cx3cr1-expressing) macrophages promoted adverse cardiac remodeling primarily in the peri-infarct zone, a vulnerable region surrounding infarct tissue” (page 31, 1st column top).Dick teaches. “Genes associated with mature macrophages (Lyve1, Timd4, Retnla, Cd163, Folr2 and Klf2) were downregulated, whereas genes associated with monocytes (Ms4a7 and Spp1) were upregulated in post-infarction macrophages, compared to noninfarcted control macrophages (Fig. 5f). “ (page 35, 2nd column 1st full paragraph).
Thus Dick teaches determining expression of Timd4 and Spp1 in macrophages and indicates Timd4 indicates the presences of resident macrophages and anticipates claim 1.
With regards to claim 2, Dick teaches, “We partitioned resident macrophages into CD68+LYVE1+Td+ and CD68+LYVE1– Td+ macrophages in the cardiac tissue sections” ((page 35, 1st column 1st full paragraph)
With regards to claim 3, Dicks teaches, “transcriptomic analysis on 1,780 individual cells was performed using the 10x Genomics platform. t-SNE dimensionality reduction analysis identified 11 major cluster” (figure 1 legend) Dicks teaches, “Differentially expressed genes defined by murine t-SNE clusters were used to determine whether sorted human cardiac macrophage populations expressed similar patterns.” (page 37, 1st column top)
With regards to claim 4-6, Dick teaches, “Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate mapping” (abstract). Dick teaches, “After myocardial infarction, the phosphatidylserine receptor TIMD4 and CCR2 emerged as mutually exclusive markers of resident macrophages and recruited macrophages, respectively. Resident macrophage abundance within the infarct zone was markedly reduced after infarction and slowly increased through in situ proliferation. Depletion of diphtheria toxin receptor–labeled resident (Cx3cr1-expressing) macrophages promoted adverse cardiac remodeling primarily in the peri-infarct zone, a vulnerable region surrounding infarct tissue” (page 31, 1st column top).
With regards to claim 7, ).Dick teaches. “whereas genes associated with monocytes (Ms4a7 and Spp1) were upregulated in post-infarction macrophages, compared to noninfarcted control macrophages (Fig. 5f). “ (page 35, 2nd column 1st full paragraph).
Summary
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/Primary Examiner, Art Unit 1683