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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/01/2026 has been entered.
Claims 22-29,31-32,35-42 are pending. Claims 41 and 42 are withdrawn. Claims 22-29,31-32 and 35-40 are under consideration.
Claim Objections
Claim 22 is objected to because of the following informalities: At line 5, “mononuclear” should read “the mononuclear” to clarify that the phagocytes being transformed are those isolated from the biological and used in the incubating step.
Claim 31 is objected to because of the following informalities: Claim is amended and now reads “low/no low or no levels of TIGAR”. It appears this should read “low or no level of TIGAR”.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 28,29,31,32,35,39,40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must 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.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In the instant case the claimed THEMS with only expression of CXCR4, CYT1P, SLC2A3 and MT2A or only lacking PLXNA1, HSPH1, CYCS and TIGAR encompassed by the claims lack a written description. The specification discusses various conditions that lead to different subtypes of macrophages including M0, Tumor conditioned macrophages, M2 and THEM. Each subtype has a different gene expression signature. Table 3 entitled “THEM identity gene expression” states that the genes in the table are univocally upregulated in THEMs vs TCM, M2 and M0 and the first genes in the table include CXCR4, CYTIP, SLC2A3 and MT2a. The claims do not require these be expressed as they recite that alternatively (and/or), all that is required is that one of (or each of, in claim 29) PLXNA2, HSPH1, CYCS and TIGAR be expressed at low or no level. The specification fails to describe THEMs that do not express CXCR4, CYTIP, SLC2A3 and MT2a, which appear to be necessary characteristics of this cell subtype that differentiates them from other subtypes of macrophages.
In view of the above considerations one of skill in the art would not recognize that applicant was in possession THEMs characterized only by the lack of expression of PLXNA2, HSPH1, CYCS and/or TIGAR.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 112b
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.
The rejection of claims 22-32,35-40 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the clarifying amendments to claims.
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 40 remains 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 40 is drawn to the macrophage of claim 29, which is drawn to a macrophage. No further limitation is added. 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.
Applicant does not appear to have addressed this rejection.
Claim Rejections - 35 USC § 102
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)(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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The rejection of claim(s) 29-31,35 and 40 remain rejected under 35 U.S.C. 102a1 as being anticipated by Ge (Front. Biol. 2012, 7(4): 359–367 DOI 10.1007/s11515-012-1237-8) is withdrawn as Ge did not teach all of the now-recited markers.
Claim(s) 22-26,28,32, 35-37,39 and 40 remain rejected under 35 U.S.C. 102a1 and a2 as being anticipated by WO2013/110817 (Mazzone) as evidenced by (Trutman, Int. J. Cancer: 77, 378–385,1998).
Mazzone taught culture of peripheral blood (biological sample, claim 23) monocytes (PBM) in HCT-conditioned media for 18 hours (claim 24), which is media conditioned through the culture of a tumor cell line (HCT116; claim 26,37). Mazzone taught culture under normoxic and hypoxic conditions (see section 5.2, page 63). With regard to claim 28, the resultant macrophage (claim 25) cells expressed CXCR4 and SLC2A3 (see page 7, page 37). With regard to claim 35, pharmaceutically acceptable carriers are discussed at page 30. With regard to newly added claim 36, Mazzone used HCT116 conditioned media and Trutmann evidences that HCT116 cells secrete M-CSF. With regard to claim 39, expression of MT2A is inherent, as all of the method steps to make the cells as required by the claims, are met by Mazzone and it was that tumor associated macrophages express MT2A.
Applicant argues that the cells of the invention have a unique gene expression pattern that is not taught by Mazzone. The Massimo declaration dated 07/01/2026 discusses that the gene-expression signature taught by Mazzone was detected in naturally occurring circulating monocytes isolated from patients with colorectal cancer (CRC) and is different from those of the instant invention. This argument is not persuasive as claims 22-26, 32 and 35 do not require any marker genes expression. For anticipation, what is required is that the art meets to claim limitations. Mazzone explicitly meets the limitations of the claims. Claim 22 requires incubation of a population of mononuclear phagocytes isolated from biological samples under hypoxic conditions in tumor cell conditioned culture media. In section 5.2, Mazzone teaches, “PBM from healthy volunteers were isolated and incubated for 18 hours with medium conditioned by either colorectal tumor cell line HCT116….Monocytes with mock medium or medium conditioned by colonic epithelial cells have a very similar expression pattern, while monocytes incubated with tumor-conditioned medium show a significant different expression pattern for these genes…there is no significant difference in expression pattern between monocytes incubated with tumor-conditioned medium in normal or hypoxic conditions.” Thus, Mazzone meets each and every claim limitation in the method of claim 22. The relevance of the expression signature of circulating macrophages isolated from CRC patients is not clear.
With regard to marker gene expression, because Mazzone explicitly teaches each and every limitation of the claimed method, the resulting cells would necessarily be the same as those resulting from the method as claimed.
Applicant points out that the changes in marker gene expression signature of macrophages cultured in normoxic and hypoxic conditions were comparable and thus, the changes were caused by the tumor-driven conditioning signals. This rationale fails to overcome the rejection. For anticipation, it is required that all claim limitations are met, which is the case, as set forth above. Mazzone states that there is no significant difference in expression pattern in cells cultured in normoxic and hypoxic conditions. This, however, fails to negate that all claim limitations are taught. If Applicant holds that the methods of the invention result in different cells than those of Mazzone, then the methods of making them should reflect at least a single difference.
Applicant states that “By contrast, THEM is not a naturally occurring monocyte population…”. In response, Mazzone teaches culturing isolated monocytes in tumor conditioned media, which is not something that occurs in nature. Applicant also argues that THEM is derived through a controlled differentiation process. This implies, perhaps, there are parameters used to control differentiation that are not recited in the claims.
Further, the method of claim 22 is carried out by Mazzone, which would inherently result in cells with the claimed marker characteristics, as supported by the specification. The method requires culture of mononuclear phagocytes, which include the monocytes of Mazzone, from a biological sample, which is blood in Mazzone, incubating the under hypoxic conditions in a culture medium comprising factors released by tumor cell lines (HCT116 cell conditioned media of Mazzone).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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