DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Arguments
2. Claims 37-55 are pending.
Claims 38 and 47 have been amended.
Claims 37-55 are examined on the merits with species (immune checkpoint inhibitors): PD-1 antagonists.
Withdrawn Grounds of Objection
Specification
3. The disclosure is no longer objected to because it no longer contains an embedded hyperlink and/or other form of browser-executable code, see Amendments to the Specification submitted March 20, 2026, page 36, lines 30-33.
Claim Objections
4. Claim 47 is no longer objected to because the plus sign beside “CD” is properly cited as a superscript, “CD4+”, see Amendments to the Claims submitted March 20, 2026, page 3 and 4 and claim 37.
Withdrawn Grounds of Rejection
Claim Rejections - 35 USC § 102
5. The rejection of claim(s) 37, 38 and 40 under 35 U.S.C. 102(a)(1) as being anticipated by Ries et al. (Cancer Cell 25: 846-859, June 16, 2014/ IDS reference #39 on sheet 3 submitted July 20, 2021) is withdrawn in light of Applicant’s arguments, as well as the fact the disclosed monoclonal antibody, RG7155 while being able to reduce colony-stimulating factor 1 receptor (CSF-1R)+CD163+ macrophages in vivo and in vitro, has no direct binding to CD163, see Remarks submitted March 20, 2026, page 9.
Claim Rejections - 35 USC § 103
6. The rejection of claim(s) 37-55 under 35 U.S.C. 103 as being unpatentable over Ries et al. (Cancer Cell 25: 846-859, June 16, 2014/ IDS reference #39 on sheet 3 submitted July 20, 2021), and further in view of Wong et al., WO 2016/069727 A1 (published 6 May 2016/ IDS reference #4 submitted July 20, 2021) and Etzerodt et al. (Journal of Controlled Release 160(1):72-80, 2012/ IDS reference #19 submitted July 20, 2021) is withdrawn in light of Applicant’s arguments, as well as the fact the disclosed monoclonal antibody, RG7155 while being able to reduce colony-stimulating factor 1 receptor (CSF-1R)+CD163+ macrophages in vivo and in vitro, has no direct binding to CD163, see Remarks submitted March 20, 2026, page 9.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 112
7. 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.
8. The rejection of claims 37-55 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 is maintained.
Applicant respectfully disagrees with the instant rejection, see Remarks submitted March 20, 2026, Claim…segment spanning pages 7 and 8. Applicant follows this point of view, stating “…the instant application discloses and defines a rat anti- mouse CD163 antibody, E10B10, which is used in a species-specific manner to reduce the population of CD163 tumor associated macrophage in mice in vivo. See, Specification at page 35 and first declaration at 11 3-5.”, see page 8 of the Remarks, 1st full paragraph (para.).
Applicant concludes arguments further stating, “…a skilled artisan would have understood at the time the instant application was filed that there were sufficient numbers of anti-CD163 antibodies available with the requisite structure and function that could be used to perform the full scope of the claims” [and the instant rejection should be withdrawn]. See, first declaration at 11 4 and 8-9 and Remarks, page 8, 1st and 2nd paragraphs (paras.).
Applicant’s points of view and arguments have been carefully considered, but fail to persuade.
While Applicant has noted the antibody disclosed in their disclosure is a rat anti-mouse CD163 antibody, E10B10, however this is not of record in the claims. As the claims currently reads on any antibody that has binding affinity for CD163. In order to facilitate the functions set forth in the claims all that is required is an antibody with binding affinity for CD163. Applicant has noted one. There is no support for the genus of antibodies encompassed by Applicant’s claims.
"[T]he purpose of the written description requirement is to "ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification." Ariad Pharm., Inc. V. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc). Where, as here, a genus is claimed using functional language to define a desired result, "the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Ariad, 598 F.3d at 1349; AbbVie Deutschland GmbH V. Janssen Biotech, Inc., 759 F.3d 1285, 1299 (Fed. Cir. 2014).
Although "functional claim language can meet the written description requirement when the art has established a correlation between structure and function," "merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species." Ariad, 598 F.3d at 1350; see also University of California V. Eli Lilly and Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997) ("A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." (alteration original) (quoting Fiers V. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993))). Further:
Regardless whether a compound is claimed per se or a method
is claimed that entails the use of the compound, the inventor
cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.
University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 926 (Fed. Cir. 2004).
The one antibody, E10B10 is not representative of the full breath of “…an antibody having binding affinity for CD163”. To show possession of the claimed methods, the genus of antibodies must be described by Applicant's Specification in accordance with 35 U.S.C. § 112(a). See Vas-Cath, 935 F.2d at 1564 ("The invention is, for purposes of the "written description" inquiry, whatever is now claimed.").
Knowledge of a target antigen is not sufficient to provide written description for the entire class of antibodies that bind to that antigen.
[T]he "newly characterized antigen" test flouts basic legal
principles of the written description requirement. Section 112 requires a "written description of the invention." But this test
allows patentees to claim antibodies by describing something
that is not the invention, i.e., the antigen. The test thus
contradicts the statutory "quid pro quo" of the patent system.
Amgen Inc. V. Sanofi, 872 F.3d 1367, 1378-79 (Fed. Cir. 2017);6 see Juno Therapeutics, Inc., V. Kite Pharma, Inc., 10 F.4th 1330, 1337 (Fed. Cir. 2021) (Considering whether a patent satisfied the written description requirement, the Juno court explained that the "patent provides nothing to indicate that the inventors possessed the full scope of the genus that they chose to claim.").
The rejection is maintained.
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 claims read on methods of treating and/or administering to an individual with cancer an antibody having binding affinity for CD163, which is an antibody conjugate in combination with an immune checkpoint inhibitor.
The written description in this instant case broadly sets forth, “the antibody suitable for depletion of CD163+ tumor associated macrophages (TAMs) is a full-length antibody. In some embodiments, the full-length antibody is an IgG1 antibody. In some embodiments, the full-length antibody is an IgG3 antibody.”, see page 22, lines 30-32 within the Specification submitted June 26, 2025. The disclosure also broadly sets forth exemplary forms of the antibody that has binding affinity for CD163, see pages 18-32.
The written description in this instant case further sets forth the antibody able to deplete CD163+ TAM are a CSF1 blocking antibody, aCD163-dxr, aCD163-LNP and/or aCD163-dxrLNP, see Figure 1 and 3 captions on pages 33 and 34; page 40; and page 44, lines 1-20. However, none of the claims recites a specific antibody clearly characterized with structure and function.
The instant application does not provide sufficient guidance as to the nexus or correlation between the structure and function of the undefined antibody having binding affinity for CD163 that places the skilled artisan in possession of the relevant identifying characteristics of a genus of antibodies thereof commensurate in scope with the claimed invention.
In Abbvie v. Centocor (Fed. Cir. 2014), the Court held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of all IL-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
“A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
Vas-Cath Inc. V Mahurkar, 19 U5PQ2d 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).
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 115).
The skilled artisan cannot envision the detailed structure of the encompassed polypeptides and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and a reference to a potential method of isolating it. The polypeptide itself is required. See Fiers v. Revel, 25 U5PQ 2d 1601 at 1606 (CAFC1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Lts. 18 U5PQ2d 1016.
Furthermore, In The Reagents of the University of California v. Eli Lilly (43 U5PQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that while Applicants are not required to disclose every species encompassed by a genus, the description of a genus is achieved by the recitation of a representative number of DNA molecules, usually defined by a nucleotide sequence, falling within the scope of the claimed genus. At section B(l), the court states that "An adequate written description of a DNA...'requires a precise definition, such as by structure, formula, chemical name, or physical properties', not a mere wish or plan for obtaining the claimed chemical invention".
At the time the application was filed Applicant seems to not be in possession of all antibodies or antigen-binding fragments thereof that have binding affinity for CD163 that is able to reduce the population of CD163+ TAMs. The specification does not evidence the possession of all antibody binding molecules, which have binding affinity for CD163 that are undefined and uncharacterized falling within the potentially large genus to establish possession. No corollary nexus has been established between structure and function.
The USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf.
The Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies, including the following.
“In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”.
There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of antibodies that have binding affinity for CD163 essential to the claimed invention to demonstrate possession that fulfill the requirements of a structure-function relationships of written description. Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).
“When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), the following is noted.
To show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358).
The instant disclosure, including the claims fail to disclose a representative number of species falling with the scope of the genus and/or structural common to the members of the genus so the one of skill in the art can visualize or recognize the members of the genus of antibodies having binding affinity for CD163. The instant disclosure, including the claims fail to disclose a representative number of antibody species falling with the scope of the genus and/or structural common to the members of the genus so the one of skill in the art can visualize or recognize the members of the genus of molecules that can facilitate therapeutic efficacy of reducing the population of CD163+. Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Here, Applicants’ claims include antibodies that encompass various structural, specificities and functional attributes to fulfill the requirements of a structure-function relationships of written description, but does not describe the structure-identifying information about the antibodies, nor describe a representative number of species falling with the scope of the genus or structural common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual said antibodies.
A skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus that exhibit this functional property.
The specification does not evidence the possession of all binding molecules that are undefined and uncharacterized falling within the potentially large genus to establish possession. Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 U5PQ2d 1398.
The full breadth of the claims do not meet the written description provision of 35 U.S.C. 112, first paragraph.
Claim Rejections - 35 USC § 103
9. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
10. The rejection of claim(s) 37-55 under 35 U.S.C. 103 as being unpatentable over Etzerodt et al. (Journal of Controlled Release 160: 72-80, online 27 January 2012/ IDS reference #19 on sheet 2 submitted July 20, 2021), and further in view of Wong et al., WO 2016/069727 A1 (published 6 May 2016/ IDS reference #4 submitted July 20, 2021) and Ries et al. (Cancer Cell 25: 846-859, June 16, 2014/ IDS reference #39 on sheet 3 submitted July 20, 2021) is maintained.
The declarations under 37 CFR 1.132 filed March 20, 2026 is insufficient to overcome the rejection of claims 37-55 based upon Etzerodt et al. (Journal of Controlled Release 160: 72-80, online 27 January 2012/ IDS reference #19 on sheet 2 submitted July 20, 2021), and further in view of Wong et al., WO 2016/069727 A1 (published 6 May 2016/ IDS reference #4 submitted July 20, 2021) and Ries et al. (Cancer Cell 25: 846-859, June 16, 2014/ IDS reference #39 on sheet 3 submitted July 20, 2021) as set forth in the last Office action because: the declarations are not commensurate in scope. The 4 page declaration, states “[a]nti-CD163 antibodies having binding affinity to the external domain of CD163…” and “[a] skilled person would have been well aware of a large number of anti-CD163 antibodies having binding affinity to the external domain of CD163 (amino acid 42-1050 of SEQ ID NO: 1), see page 3, segments 8 and 10, respectively. The claims broadly read on “…an [or the] antibody having binding affinity for CD163”, see in particular claims 37 and 45.
Furthermore, the 7 page declaration is not commensurate in scope as it declares “…an anti-CD163 antibody to deplete the CD163+ TAM subset in a mouse cancer model (YUMM1.7, melanoma cells)”, see page 3, segment 13. However, independent claims 37 and 45 read on any and all cancers.
Accordingly, neither declaration is sufficient to overcome the instant obvious type rejection.
In addition, Applicant’s arguments do not seem to read on the instant combination of prior art that teaches the claimed invention, see Remarks submitted March 20, 2026, pages 10-15. All arguments read on Ries as the primary reference, see in particular page 10, 1st full paragraph (para.); page 11; page 12, 2nd and 3rd paragraphs (paras.); and para. bridging pages 12 and 13. However, for expediency of prosecution the Examiner will respond to the instant Remarks.
Applicant argues “…Etzerodt …[does not]… cure the deficiencies of Ries and/or Wong because although they teach the use of an anti-CD163 antibody to target CD163 positive cells, neither teaches the use of their anti-CD163 antibody in the melanoma cancer model of the present application. (See, Etzerodt and Graversen, throughout documents)[.] Furthermore, … Etzerodt … [teaches] that there are subsets of TAM that express different levels of CD163 that would teach a skilled artisan to understand that different cancers may respond differently to the use of an anti-CD163 antibody to deplete TAM. (see, second declaration at 11 4-6, 12, 20, and 23- 25) [.]”, see Remarks submitted March 20, 2026, 1st para. on page 13.
Applicant further argues their claimed method shows surprising results, significantly decreasing tumor volume compared to pan TAM depletion by an anti-CSF-1 antibody and “…that the anti-CD163 antibody, which depletes only a subset of TAM in melanoma cancer model, reduced tumor volume and increased TIL significantly more that the pan macrophage anti-CSF-1 antibody, which depletes all TAM subsets.”, see page 13, last para.; and page 14, 2nd paragraph.
The 4 page declaration lists the anti-CD163 antibodies known to persons of ordinary skill in the art and it include the antibody, E10B10 of the prior art, Etzerodt in the Table. Applicant submits the 2012 Etzerodt paper, the prior art herein teaches the species-specific antibody that targets CD163, see segments 5 and 6 on page 2 of said declaration. Accordingly, the rejection is maintained as antibody is the same as that in the claims thereby rendering the same effects espoused in the claims.
The combination of references teaches the claimed invention.
The combination of these teachings do not differ from Applicant’s claimed invention, nor what is exemplified in Applicant’s teachings herein. The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious.
Moreover, the modification of the primary reference in light of the secondary references is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213
USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old
elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art
invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. For the reasons of record and cited herein, the rejection is maintained.
Etzerodt teaches “…liposomes specifically targeting CD163 by hydrophobic linkage of CD163-binding monoclonal antibodies to polyethylene glycol-coated liposomes (‘stealth liposomes’).”, see page Abstract on page 72. The CD163 targeting liposomes were loaded with calcein, as well as “…the chemotherapeutic agent doxorubicin as cargo of the liposomes.”, see Abstract on page 72. Liposomal doxorubicin modified for CD163 targeting (doxLCL-a-CD163) and targeted calcein-loaded LCLs (calLCL) modified with rat IgG anti-mouse CD163 antibody, calLCL-a-CD163 (E10B10), see segments 3.3 and 3.4 on page 77. The long-circulating liposomes (LCLs) with encapsulated calcein and doxorubicin is regarded as a lipid-nanoparticle (LNP).
It would naturally flow with the administration of the Etzerodt CD163 antibody, the population of CD163+ tumor associated macrophages (TAMs) would be reduced with the subsequent increase in the amount of tumor infiltrating T cells (TILs).
Etzerodt does not explicitly teach measuring an increase in the amount of TILs after the population of CD163+ TAMs is reduced with the administration of the Etzerodt CD163-targeting liposomal doxorubicin to treat cancer including melanoma, wherein the increase of TILs T cells, CD8+ T cells or CD4+ T cells are measured and the reduction of CD163+.
Nor, does Etzerodt teach a method, wherein the CD163 targeting LNP comprising doxorubicin is administered in combination with an immune checkpoint inhibitor to treat cancer, melanoma.
However, Wong teaches a method of administering an antibody able to reduce immunosuppressive tumor-associated macrophages (TAMs), as well as combination therapy with an anti-CSFIR antibody and anti-neoplastic composition(s) including PD-1/PD-L1 inhibitors and/or chemotherapy, see page 8, section 020; section 045 bridging pages 15 and 16; page 32, section 0107.
Wong teaches melanoma can be treated with the administration of the anti-CSF1R antibody and a PD-1/PD-L1 inhibitor, see section 014 bridging pages 4 and 5; page 6, lines 6-9. PD-1/PD-L1 inhibitors include “CTLA-4 inhibitors (e.g., anti-CTLA antibody ipilimumab (YERVOY®)), PD-1 inhibitors (e.g., anti-PD-1 antibodies, BMS-936558), PD-L1 inhibitors (e.g., anti-PD-L1 antibodies, MPDL3280A), …, TIM3 inhibitors (e.g., anti-TIM3 antibodies), …antagonists (e.g., neutralizing antibodies) that bind to one or more of the following targets…, PD-1, PD-L1, …, CTLA-4, TIM3, …”, see page 32, section 0107.
Wong does teach immune filtrates from tumor biopsy specimens will be evaluated before treatment, as well as on treatment, see page 145, section 0940. Wong does not teach the antibody is conjugated to a lipid-nanoparticle (LNP).
Ries teaches the same antibody as Wong, CSF-1R antibody,a monoclonal antibody, RG7155 is able to reduce colony-stimulating factor 1 receptor (CSF-1R)+CD163+ macrophages in vivo and in vitro, and CD68+163+, see Summary on page 846; page 847, 1st column (col.), 2nd paragraph (para.) and 2nd col., RG7155…segment; page 849, 1st col., 1st full para. and 2nd col., last para.; and page 851, RG7155…segment. RG7155 is a humanized CSF-1R antibody. The anti-CSF1R of Wong is regarded as an antibody having binding affinity for CD163.
Ries further teaches after the administration of the antibody there was a measured increase of subtypes of tumor-infiltrating T cells (TILs) including lymphocytes, natural killer (NK) cells, CD4+ T cells, CD8+ T cells, CD8+/CD4+, see Figure 4 and in particular, Figure 4(B) on page 853. “Mice were treated twice (days 7 and 14 after tumor inoculation), and tumor infiltrate was analyzed on day 16 by flow cytometry (A and B) or immunohistochemistry [Figure 4] (C).”, see Figure 4 on page 853. There was “…a relative increase of other types of immune cells including Ly6Ghigh neutrophils, natural killer (NK) cells, and both CD4+ and CD8+ T cells (Figures 4A, 4B, S3F, and S3G).”, see Mouse…segment spanning both columns (cols.) on page 849.
“The baseline T cell infiltrate was dominated by CD4+ T cells and switched to a predominantly CD8+ lymphocyte infiltrate upon therapy. This is reflected in the increased CD8/CD4 ratio in five out of seven patients treated with RG7155 (Figure 6C), thus mirroring observations in mouse models and analyzed by immunohistochemistry (IHC), see page 851, 1st col., 1st para.; and page 856, Figure 6.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Etzerodt, Wong and Ries to implement the antibody conjugate including a cytotoxic moiety and LNP that targets CD163 in the method of treating treat cancer including melanoma. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in the references that CD163 antibody conjugates are able to target TAMs of the M2 phenotype and Tie2 positive monocytes, which both have high CD163 expression and directly linked to tumor progression, see page 79 of Etzerodt, bridging paragraph of both cols. and the graphical abstract; and all references in their entirety.
It also would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teaching of Etzerodt, Wong and Ries to administer the CD163 antibody of Etzerodt with an immune checkpoint inhibitor to treat cancer including melanoma. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in the references that combination therapies directed to “…tumor entities in which TAMs contribute to tumor pathogenesis” may be beneficial, see Ries, Significance on page 846; and page 855, para. bridging cols. 1 and 2; and entire document, as well as all references in their entirety.
Etzertodt Graphical abstract
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11. The rejection of claim(s) 37-55 under 35 U.S.C. 103 as being unpatentable over Graversen et al., US 2012/0258107 A1 (published October 11, 2012), and further in view of Etzerodt et al. (Journal of Controlled Release 160: 72-80, online 27 January 2012/ IDS reference #19 on sheet 2 submitted July 20, 2021), Wong et al., WO 2016/069727 A1 (published 6 May 2016/ IDS reference #4 submitted July 20, 2021) and Ries et al. (Cancer Cell 25: 846-859, June 16, 2014/ IDS reference #39 on sheet 3 submitted July 20, 2021) is maintained.
The declarations under 37 CFR 1.132 filed March 20, 2026 is insufficient to overcome the rejection of claims 37-55 based upon Graversen et al., US 2012/0258107 A1 (published October 11, 2012), and further in view of Etzerodt et al. (Journal of Controlled Release 160: 72-80, online 27 January 2012/ IDS reference #19 on sheet 2 submitted July 20, 2021), Wong et al., WO 2016/069727 A1 (published 6 May 2016/ IDS reference #4 submitted July 20, 2021) and Ries et al. (Cancer Cell 25: 846-859, June 16, 2014/ IDS reference #39 on sheet 3 submitted July 20, 2021) as set forth in the last Office action because: the declarations are not commensurate in scope. The 4 page declaration, states “[a]nti-CD163 antibodies having binding affinity to the external domain of CD163…” and “[a] skilled person would have been well aware of a large number of anti-CD163 antibodies having binding affinity to the external domain of CD163 (amino acid 42-1050 of SEQ ID NO: 1), see page 3, segments 8 and 10, respectively. The claims broadly read on “…an [or the] antibody having binding affinity for CD163”, see in particular claims 37 and 45.
Furthermore, the 7 page declaration is not commensurate in scope as it declares “…an anti-CD163 antibody to deplete the CD163+ TAM subset in a mouse cancer model (YUMM1.7, melanoma cells)”, see page 3, segment 13. However, independent claims 37 and 45 read on any and all cancers.
Accordingly, neither declaration is sufficient to overcome the instant obvious type rejection.
In addition, Applicant’s arguments do not seem to read on the instant combination of prior art that teaches the claimed invention, see Remarks submitted March 20, 2026, pages 10-15. All arguments read on Ries as the primary reference, see in particular page 10, 1st full paragraph (para.); page 11; page 12, 2nd and 3rd paragraphs (paras.); and para. bridging pages 12 and 13. However, for expediency of prosecution the Examiner will respond to the instant Remarks.
Applicant argues “…Graversen …[does not]… cure the deficiencies of Ries and/or Wong because although they teach the use of an anti-CD163 antibody to target CD163 positive cells, neither teaches the use of their anti-CD163 antibody in the melanoma cancer model of the present application. (See, Etzerodt and Graversen, throughout documents)[.] Furthermore, … Graversen… [teaches] that there are subsets of TAM that express different levels of CD163 that would teach a skilled artisan to understand that different cancers may respond differently to the use of an anti-CD163 antibody to deplete TAM. (see, second declaration at 11 4-6, 12, 20, and 23- 25) [.]”, see Remarks submitted March 20, 2026, 1st para. on page 13.
Applicant further argues their claimed method shows surprising results, significantly decreasing tumor volume compared to pan TAM depletion by an anti-CSF-1 antibody and “…that the anti-CD163 antibody, which depletes only a subset of TAM in melanoma cancer model, reduced tumor volume and increased TIL significantly more that the pan macrophage anti-CSF-1 antibody, which depletes all TAM subsets.”, see page 13, last para.; and page 14, 2nd paragraph.
The 4 page declaration lists the anti-CD163 antibodies known to persons of ordinary skill in the art and it include the antibody, E10B10 of the prior art, Etzerodt in the Table. Applicant submits for all intents and purposes the antibodies of Graversen, Mac 2-48, Mac 2-49, Ber-MAC3 are the anti-CD163 well known at the time the instant application was filed, see 4 page declaration, segments 7, 8 and 9 and Table spanning pages 3 and 4 of the said declaration. The prior art, Graversen herein teaches the species-specific antibody that targets CD163, see segments 7-9 and the table spanning pages 2 and 4 of said declaration. Accordingly, the rejection is maintained as antibody is the same as that in the claims thereby rendering the same effects espoused in the claims.
The combination of references teaches the claimed invention.
The combination of these teachings do not differ from Applicant’s claimed invention, nor what is exemplified in Applicant’s teachings herein. The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious.
Moreover, the modification of the primary reference in light of the secondary references is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213
USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old
elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art
invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. For the reasons of record and cited herein, the rejection is maintained.
Graversen teaches methods of treating conditions or disorders, such as cancer cells expressing CD163 and melanoma with an agent, see page 14, section 0201. The agent may comprise a binding moiety, such as an antibody with binding specificity for an extracellular scavenger receptor cysteine-rich (SRCR) domain 1 of the CD163 receptor, see page 1, sections 0001, 0008, 0015-0017; and sections 0047-0049, 0052 spanning pages 5 and 6. CD163 antibodies taught within Graversen include “(e.g. Mac2-48, Mac2-158, 5C6FAT, BerMac3)”, see page 11, section 0163; and page 12, sections 0168 and 0169. The antibody further comprises a cytotoxic moiety, doxorubicin, see page 13, sections 0187 and 0192.
Graversen does not teach the method, wherein the taught antibody is administered with an immune checkpoint inhibitor to treat cancer including melanoma. Graversen does not teach their antibody is conjugated to a lipid-nanoparticle (LNP).
Graversen does not teach measuring an increase in the amount of TILs after the population of CD163+ TAMs is reduced with the administration of the said CD163-targeting liposomal doxorubicin to treat cancer including melanoma, wherein the increase of TILs T cells, CD8+ T cells or CD4+ T cells are measured and the reduction of CD163+.
However, Etzerodt teaches “…liposomes specifically targeting CD163 by hydrophobic linkage of CD163-binding monoclonal antibodies to polyethylene glycol-coated liposomes (‘stealth liposomes’).”, see page Abstract on page 72. The CD163 targeting liposomes were loaded with calcein, as well as “…the chemotherapeutic agent doxorubicin as cargo of the liposomes.”, see Abstract on page 72. Liposomal doxorubicin modified for CD163 targeting (doxLCL-a-CD163) and targeted calcein-loaded LCLs (calLCL) modified with rat IgG anti-mouse CD163 antibody, calLCL-a-CD163 (E10B10), see segments 3.3 and 3.4 on page 77. The long-circulating liposomes (LCLs) with encapsulated calcein and doxorubicin is regarded as a lipid-nanoparticle (LNP).
Wong further teaches a method of administering an antibody able to reduce immunosuppressive tumor-associated macrophages (TAMs), as well as combination therapy with an anti-CSFIR antibody and anti-neoplastic composition(s) including PD-1/PD-L1 inhibitors and/or chemotherapy, see page 8, section 020; section 045 bridging pages 15 and 16; page 32, section 0107.
Wong teaches melanoma can be treated with the administration of the antibody and a PD-1/PD-L1 inhibitor, see section 014 bridging pages 4 and 5; page 6, lines 6-9. PD-1/PD-L1 inhibitors include “CTLA-4 inhibitors (e.g., anti-CTLA antibody ipilimumab (YERVOY®)), PD-1 inhibitors (e.g., anti-PD-1 antibodies, BMS-936558), PD-L1 inhibitors (e.g., anti-PD-L1 antibodies, MPDL3280A), …, TIM3 inhibitors (e.g., anti-TIM3 antibodies), …antagonists (e.g., neutralizing antibodies) that bind to one or more of the following targets…, PD-1, PD-L1, …, CTLA-4, TIM3, …”, see page 32, section 0107.
Wong does teach immune filtrates from tumor biopsy specimens will be evaluated before treatment, as well as on-treatment, see page 145, section 0940.
And Ries teaches the same antibody as Wong, CSF-1R antibody,a monoclonal antibody, RG7155 is able to reduce colony-stimulating factor 1 receptor (CSF-1R)+CD163+ macrophages in vivo and in vitro, and CD68+163+, see Summary on page 846; page 847, 1st column (col.), 2nd paragraph (para.) and 2nd col., RG7155…segment; page 849, 1st col., 1st full para. and 2nd col., last para.; and page 851, RG7155…segment. RG7155 is a humanized CSF-1R antibody.
Ries further teaches after the administration of the antibody there was a measured increase of subtypes of tumor-infiltrating T cells (TILs) including lymphocytes, natural killer (NK) cells, CD4+ T cells, CD8+ T cells, CD8+/CD4+, see Figure 4 and in particular, Figure 4(B) on page 853. “Mice were treated twice (days 7 and 14 after tumor inoculation), and tumor infiltrate was analyzed on day 16 by flow cytometry (A and B) or immunohistochemistry [Figure 4] (C).”, see Figure 4 on page 853. There was “…a relative increase of other types of immune cells including Ly6Ghigh neutrophils, natural killer (NK) cells, and both CD4+ and CD8+ T cells (Figures 4A, 4B, S3F, and S3G).”, see Mouse…segment spanning both columns (cols.) on page 849.
“The baseline T cell infiltrate was dominated by CD4+ T cells and switched to a predominantly CD8+ lymphocyte infiltrate upon therapy. This is reflected in the increased CD8/CD4 ratio in five out of seven patients treated with RG7155 (Figure 6C), thus mirroring observations in mouse models and analyzed by immunohistochemistry (IHC), see page 851, 1st col., 1st para.; and page 856, Figure 6.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Graversen, Etzerodt, Wong and Ries to manufacture and implement the antibody conjugate including a cytotoxic moiety and LNP that targets CD163 in the method of treating treat cancer including melanoma. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in the references that CD163 antibody conjugates are able to target TAMs of the M2 phenotype and Tie2 positive monocytes, which both have high CD163 expression and directly linked to tumor progression, see page 79 of Etzerodt, bridging paragraph of both cols. and the graphical abstract; and all references in their entirety.
It also would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teaching of Graversen, Etzerodt, Wong and Ries to administer the CD163 antibody of Graversen or Etzertodt with an immune checkpoint inhibitor to treat cancer including melanoma. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in the references that combination therapies directed to “…tumor entities in which TAMs contribute to tumor pathogenesis” may be beneficial, see Ries, Significance on page 846; and page 855, para. bridging cols. 1 and 2; and entire document, as well as all references in their entirety.
It also would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teaching of Graversen, Etzerodt, Wong and Ries to measure the increase of TILs after CD163+ TAMs were reduced by the CD163 antibody conjugate and/or CD163 antibody conjugate with an immune checkpoint inhibitor. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in the references that these measures aid in determining whether or not the treatment was effective, see all references in their entirety and in particular Wong and Ries.
Etzertodt Graphical abstract
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Conclusion
12. THIS ACTION IS MADE FINAL. 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.
13. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached 8AM-8PM, Monday through Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
May 8, 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643
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