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 1-9, 11-12, 14-19, 21, and 23-24 are pending.
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 24 January 2026 has been entered.
Status of the Application
Applicant’s response and amendment filed 24 January 2026 are acknowledged and entered.
Applicant has amended Claims 1 and 11.
Response to Amendment
The 112a New Matter rejection is withdrawn.
The 112a scope of enablement rejection is maintained and modified updated.
The 103 rejections are maintained but updated in response to the claim amendments.
Claims 1-9, 11-12, 14-19, 21, and 23-24 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
Claim Interpretation
The claims now recite that the melanoma is subcutaneous. The Spec. does not provide any special definition for subcutaneous. Therefore subcutaneous is interpreted in its broadest reasonable sense: underneath the skin which encompasses cancer in organs.
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 11-12, 14, and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for slowing the growth of melanoma cells in vivo, does not reasonably provide enablement for a method for slowing the growth of melanoma cells in vitro. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection. This rejection is maintained and updated.
The factors to be considered in determining whether a disclosure would require undue experimentation include: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the specification; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and the nature of the invention: With respect to claim breadth, the standard under 35 U.S.C. §112(a) entails determining what the claims recite and what the claims mean as a whole. Claims 11-12, 14, and 24 recite a method for slowing the growth of melanoma cells in vitro, the method comprising contacting the melanoma cells with a composition comprising: 1) a nucleic acid sequence that encodes Gal-3; and/or 2) a vector comprising a nucleic acid sequence that encodes Gal-3; and measuring the number and size of colonies formed by the melanoma cells, the melanoma cells being resistant to an ICI; and measuring the expression levels of NFAT1 in the melanoma cells (Claim 11), the cells being metastatic (Claim 12), wherein the cells are resistant to the ICI that is an antibody to CTLA-4 (Claim 14), and wherein the composition further comprises GB1211 (Claim 24).
The broadest reasonable interpretation of the methods is that by contacting melanoma cells, metastatic melanoma cells, or CTLA-4–resistant melanoma cells, the growth of melanoma cells in vitro will be slowed.
A skilled artisan would not be able to use the method as claimed with a reasonable expectation of success based solely on what is disclosed in the specification.
The state of the prior art, the level of one of ordinary skill, and the level of predictability in the art: The prior art of Hayashi (et al. 2019. Galectin-3 Inhibits Cancer Metastasis by Negatively Regulating Integrin β3 Expression. Am. J. Pathol. 189[4]:900-910, “Hayashi”, of record) shows that while expressing Gal-3 in melanoma cells slows growth via slowing metastasis in mice in vivo, expressing Gal-3 cells in metastatic melanoma cells grown in vitro actually can increase the cell number. Hayashi’s Fig. 7B shows increased expression in metastatic melanoma cell line A2058 and Fig. 7C shows that there are more of those cultured cells within the same time period:
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A further survey of the art found that while many studies show what occurs to melanoma or metastatic melanoma cell growth in vitro when Gal-3 is knocked out, Hayashi is the only study identified that shows what occurs when cells are made to express Gal-3.
Hayashi’s data demonstrate that amount of Gal-3 expression in cells in in vivo experiments does not predict what occurs in in vitro experiments and vice versa. Related to Gal-3 overexpression in the same A2058 cells, despite Gal-3 overexpression increasing cell numbers in vitro, overexpression actually decreased number of metastatic foci in vivo (see Figs. 7EF). Similarly, Hayashi’s Fig. 2D shows that Gal-3 knockout (KO) slightly decreased number of cells in vitro but Figs. 2FG show Gal-3 KO increased tumor metastasis in vivo. That demonstrates that Gal-3 expression or lack of expression can affect cells differently depending on whether cells exist in an in vitro or in vivo context.
Furthermore, it is known in the art that knockout/knockdown phenotypes do not reliably predict overexpression phenotypes. For example, Prelich (2012. Gene Overexpression: Uses, Mechanisms, and Interpretation. Genetics 190[3]:841-854, “Prelich”) teaches (§Distinguishing the mechanisms-Determining the loss-of-function phenotype ¶1):
The primary test to distinguish the mechanism responsible for an overexpression phenotype is determining the loss-of-function phenotype of the gene of interest. Three outcomes can be envisioned: loss-of-function could cause either the opposite phenotype of overexpression, the same phenotype, or no phenotype. The simplest scenario to interpret is when overexpression and deletion cause opposite phenotypes… [emphasis added.]
That indicates that opposite phenotypes are “the simplest scenario to interpret”. But Prelich also teaches (same §, ¶2) in contrast with the previous examples, overexpression of the wild-type gene can also cause identical phenotypes as loss-of-function mutations [emphasis added]. Prelich teaches another scenario (same §, ¶3) a final scenario is when a gene that causes an overexpression phenotype has no obvious deletion phenotype.
All of the outcomes Prelich discusses start with knowing the overexpression phenotype, but a person of ordinary skill should readily understand how the exact same principles apply to a situation in which the knockdown phenotype is known and the overexpression phenotype is sought (i.e., a case like that of the instant claims and what is shown in the instant Spec.; see below §The amount of direction provided by the specification and the existence of working examples). That is why Prelich concludes (§Summary and Future Directions ¶1) with the general assessment that: A lesson emerging from systemic knockout studies is that loss-of-function mutations alone are insufficient to deduce gene functions [emphasis added]. Therefore Prelich indicates that it is not possible to predictably extrapolate an overexpression phenotype from a knockdown/knockout phenotype.
Hayashi’s data and Prelich’s teachings indicate that, without presentation of evidence demonstrating that Gal-3 overexpression slows melanoma cell growth in vitro, an artisan would determine that the invention of Claims 11-12, 14, and 24—which claims the opposite of what is known in the art (Hayashi) and has no evidence to substantiate the claims—is unpredictable.
The amount of direction provided by the specification and the existence of working examples: What is enabled by the working examples in the Spec. is narrow compared to the breadth of the claims. The examples do not show any experiments that demonstrate what happens to melanoma cell growth in vitro when Gal-3 is overexpressed in melanoma cells. The Spec.’s examples show changes in expression and downstream gene expression but not growth. The examples show what Gal-3 knockdown (KD) does to cell growth, but not overexpression.
Example 1 (starts p. 53; Figs. 1 and 9) discusses that Gal-3 is downregulated in metastatic melanoma.
Example 2 (starts p. 54; Figs. 2AB) discusses that melanoma patients have higher levels of circulating Gal-3, but that does not correlate with tumor progression.
Example 3 (starts p. 56; Figs. 2CD) discusses that Gal-3 is expressed by other non-melanoma cells in the TME.
Example 4 (starts p. 56; Figs. 3 and 6-7) discusses that ablating Gal-3 in melanoma cells enhances the metastatic behavior. Fig. 7 shows mice injected with Gal3KD cells have a higher tumor burden than mice injected with control cells. All of those data are from either KD experiments or KD experiments in vivo. None of those data show what happens—let alone to growth of melanoma cells in vitro—when Gal-3 is artificially expressed or overexpressed in melanoma cells.
Example 5 (starts p. 57; Figs 4, 8, 10) discusses that Gal-3 silencing activates certain prosurvival molecules (Figs. 4AB). The example discusses that Applicants produced a cell line that stably overexpresses Gal-3 (Figs. 8AB) and that overexpression resulted in suppression of the same prosurvival pathways that were upregulated in the absence of Gal-3 (Figs. 4C). The example discusses that metastatic melanoma cells have upregulated NFAT expression (Figs. 4DE) and Gal-3 expression is negatively (i.e., inversely) correlated with NFAT expression (Fig. 4F). The example discusses that the effect of Gal3 knockdown was further studied in Gal3KD cell lines (Figs. 4GH, 8CD) and that another experiment shows overexpressing Gal-3 resulted in reduced NFAT (Figs. 4I, 8E). The example discusses that other effector proteins were upregulated in Gal3KD cells vs. control cells (Figs. 8FG). The example discusses that other cancer-related signaling pathways are altered in Gal3KD cells (Fig. 10). Nearly all of those data are from KD experiments. Only some of those data describe what occurs when Gal-3 is overexpressed (those figures relevant to overexpression are bolded/underlined in this ¶), and none of those experiments touches on whether or not in vitro cell growth is slowed.
Example 6 (starts p. 59; Figs. 5 and 11) discusses what happens to another target in the pathway when Gal3 is knocked down. All of those data are from either KD experiments or KD experiments in vivo. None of those data show what happens—let alone to growth of melanoma cells in vitro—when Gal-3 is artificially expressed or overexpressed in melanoma cells.
Altogether, those experiments show what happens when Gal-3 is knocked down. Those experiments show that over-expressing Gal-3 in melanoma cells in vitro changes expression of some genes. However, none of the experiments show that expressing Gal-3 in melanoma cells results in the claimed outcome of slowing the growth of melanoma cells in vitro. That is because none of the experiments in the Spec. tested how expressing (rather than knocking down) Gal-3 in melanoma cells in vitro affects melanoma cell growth.
Since Applicant’s data do not show how artificial expression or overexpression of Gal-3 affects cell growth in vitro, it is necessary to turn to what is shown in the art. As discussed above, the art of Hayashi demonstrates that how artificial Gal-3 expression or overexpression in melanoma cells affects melanoma cell growth in vitro either conflicts with claimed outcome recited in Claims 11-12, 14, and 24 (i.e., Hayashi’s Fig. 7) or else is unpredictable. Therefore, although the skill level of an artisan is high, the art of slowing melanoma cell growth in vitro by contacting the melanoma cells with a composition comprising something that gets the cells to express Gal-3 is unpredictable. Therefore a person of ordinary skill in the art would necessarily determine that the method could not be used as claimed to slow melanoma cell growth in vitro.
The quantity of experimentation needed to make or use the invention: The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given Hayashi’s experimental evidence to the contrary regarding the effects of expressing Gal-3 on melanoma cell growth in vitro and given that Applicant has not presented any data showing that expressing Gal-3 slows melanoma cell growth in vitro, an artisan of ordinary skill would not be able to use the invention as claimed with a reasonable expectation of success. The amount of experimentation required for enabling guidance commensurate in scope with what is claimed goes beyond what is considered “routine” within the art and constitutes undue further experimentation in order to successfully use the method of slowing melanoma cell growth in vitro by contacting the melanoma cells with a composition comprising a nucleic acid sequence or vector encoding Gal-3 with a reasonable expectation of success. Claims 11-12 and 14 are rejected for those reasons and Claim 24 is rejected because it depends from Claim 11 and does not remedy the issues.
The following is enabled:
a method for slowing the growth of melanoma cells in vivo, the method comprising contacting the melanoma cells with a composition comprising: 1) a nucleic acid sequence that encodes Gal-3; and/or 2) a vector comprising a nucleic acid sequence that encodes Gal-3; and measuring the number and size of colonies formed by the melanoma cells, the melanoma cells being resistant to an ICI; and measuring the expression levels of NFAT1 in the melanoma cells.
Claim Rejections - 35 USC § 103
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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Hayashi (of record), Brown (et al. 2012. Association of galectin-3 expression with melanoma progression and prognosis. Eur. J. Canc. 48:865-874, “Brown”, of record on IDS), Gregory (of record), Goldmacher (and Conklin. 2012. The use of tumour volumetrics to assess response to therapy in anticancer clinical trials. Br. J. Clin. Pharmacol. 73[6]:846-854, “Goldmacher”, of record), Mozzillo (2021. Overview of Subcutaneous Metastatic Melanoma. Cancers 13[9]:2063, “Mozillo”), Baraldi (et al. 2013. Growth and form of melanoma cell colonies. J. Stat. Mech. P02032, “Baraldi”, of record), and Zhang (of record),. This rejection has been updated in response to the claim amendments.
Hayashi teaches that overexpression of Gal-3 in melanoma cells suppresses metastasis. Hayashi is drawn to Gal-3’s inhibition of cancer metastasis via negative regulation of integrin β3 expression. Hayashi used B16 or B16/6 cells which are mouse melanoma cells and (see below) A2058 cells which are human melanoma cells.
Hayashi teaches (§Abstract):
… highly metastatic mouse melanoma B16/BL6 cells express less Gal-3 than B16 cells with a lower metastatic potential… overexpression of Gal-3 in melanoma cells in fact suppresses metastasis. In contrast, knocking out Gal-3 expression in cancer cells … increased the number of metastatic foci in vivo. Thus, reduced Gal-3 expression results in the up-regulation of b3 integrin expression, and this contributes to metastatic potential. [emphasis added.]
Hayashi teaches (§Results-Gal-3 expression alters the potential for tumor metastasis ¶1) the highly metastatic mouse melanoma variant B16/BL6 had lower [Gal-3] expression than poorly metastatic B16 cells, both at the mRNA and protein levels (Figure 1A). Hayashi teaches when Gal-3 expression was forced in the metastatic melanoma cells and the cells were injected into mouse tail veins, Gal-3 expression resulted in significantly fewer metastatic foci:
…Gal-3 expression was enforced in B16/BL6 cells (Figure 1B). An in vivo experimental metastasis model in which B16/BL6 cells, B16/BL6-mock cells, or B16/BL6 cells in which Gal-3 expression was enforced were injected into the tail veins of recipient mice was used. After 3 weeks, the number of pulmonary metastatic foci was counted. B16/BL6 cells in which Gal-3 expression was enforced generated a lower number of metastatic foci than the parental B16/BL6 cells (Figure 1, C and D). [emphasis added.]
An excerpt of Fig. 1 is shown here:
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§Materials and methods-Plasmid Construction and transfection) teaches that cDNA encoding Gal-3 was expressed in cells from a vector. That indicates that expressing a nucleic acid encoding Gal-3 from a vector reduced melanoma tumor growth in a mouse subject. The melanoma cells were injected into the tail and developed in the lungs. Those are some limitations of Claim 1.
Hayashi teaches that overexpression of Gal-3 in human metastatic melanoma cell lines (i.e., A2058–Gal-3) injected to mice suppressed cancer metastasis: (§Tumor Cell Metastasis Is Affected by Gal-3 in Human Melanoma Cells) when cells were injected into the tail veins of nude mice, overexpression of Gal-3 suppressed cancer cell metastasis in the lung, as was observed for B16 melanoma cells (Figure 7, E and F). Figs. 7EFs are shown here:
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Fig. 7E (quantified in Fig. 7F) shows many fewer melanoma metastases were found in lungs when melanoma cells also express Gal-3.
Hayashi’s finding that expressing Gal-3 in tumor cells led to fewer metastatic foci shows that slowing of melanoma cell growth in an organism is an outcome of expressing Gal-3 in a tumor. By reducing the total number of metastatic foci total cell growth over time is slowed. Overall, Hayashi teaches that (§Discussion ¶2) …in contrast to a previous report suggesting that Gal-3 induces malignant tumor growth associated with cancer cell proliferation, Gal-3 expression was found to inhibit malignant progression of the tumor by reducing metastasis. Furthermore, significantly fewer metastases indicates reduced tumor growth in vivo. Therefore Hayashi teaches a method for reducing melanoma tumor growth in a subject by administering a pharmaceutical composition comprising cells modified with a nucleic acid encoding Gal-3 and a method for slowing growth of melanoma cells in vivo (i.e., by reducing overall number of metastatic foci).
Regarding Claims 2 and 18: Hayashi teaches (§Materials and Methods-Tumor Growth and Metastasis in Vivo) a PBS vehicle was used to inject cells for in vivo tumor models to mouse tail vein. PBS + active ingredient can be considered a pharmaceutical composition. IV injection is one kind of parenteral administration (i.e., a limitation of Claims 2 and 18).
In addition to the teachings of Hayashi, those of Brown, drawn to an association of Gal-3 expression with melanoma progression and prognosis, would have motivated an artisan to express Gal-3 to treat melanoma or reduce tumor growth. Brown teaches (§Abstract-Results) there is a progressive decrease in Gal-3 expression between thin primary melanomas and thicker melanomas or metastatic melanomas. Brown teaches (same §) strong Gal-3 expression was associated with overall survival and melanoma-specific survival. Brown teaches (§Abstract-Conclusion) Gal-3 is a marker of progression in melanocytic lesions and a novel prognostic marker in primary melanomas. Brown teaches (§3.3 Survival analysis ¶1; Fig. 3) the most favourable survival was seen in those patients with the highest nuclear [Gal]-3 expression and the least favourable survival was seen in those with the lowest nuclear [Gal]-3 expression. Brown acknowledges (§4. Discussion ¶2-3) data on the expression of Gal-3 in cancer are conflicting… and the relationship between [Gal]-3 expression and survival in cancer is also somewhat conflicting but still concludes that (same §, ¶4) their survival analysis revealed that elevated [Gal]-3 expression was associated with an improved overall and melanoma-specific survival in patients with primary melanoma.
In view of the teachings of Hayashi and Brown it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer a nucleic acid or vector encoding Gal-3 for the benefits of reducing melanoma metastasis, and thereby reducing melanoma tumor growth and slowing overall melanoma cell growth in vivo. One would have been motivated to do so with a reasonable expectation of success because Hayashi showed that (Figs. 1 and 7) expressing Gal-3 reduces number of metastatic foci and because Brown showed (1) a statistical relationship between Gal-3 expression in melanoma and cancer metastatic potential and (2) that higher levels of Gal-3, particularly in the nucleus, statistically correlate with increased overall and disease-specific survival. Although both Hayashi and Brown acknowledge that the relationship between Gal-3 expression and melanoma can be confusing, and teaches (Hayashi §Discussion ¶3) whether malignant tumor progression is more strongly facilitated by intra- or extracellular Gal-3 is not clearly determined, both references teach a clear relationship between higher Gal-3 expression within melanoma cells and (Hayashi) reduced melanoma metastasis and (Brown) increased disease-specific survival as well as (both references) lower Gal-3 expression in metastatic melanoma.
Hayashi and Brown do not teach merely administering a pharmaceutical composition comprising a nucleic acid encoding Gal-3 (i.e., without modifying cells).
However, Gregory teaches gene therapy for treating cancer. Gregory is drawn to modulating the expression of tumor suppressor genes using activating oligonucleotide technologies as a therapeutic approach in cancer. Gregory teaches (§Introduction-What are tumor suppressor genes ¶4):
The continuum model of tumor suppression … suggests that even subtle changes in the expression of a TSG can impact its function and tumor-suppressive activity.39 This model takes into consideration the fact that genes can be regulated in ways other than by mutation or allele loss, such as by epigenetic modifications, microRNAs and post-translational modifications. These changes can result in altered expression of the gene, but the gene itself is not mutated. This means that the transcription and translation of the gene produces a normal, functional protein, but the levels of the protein are lower in the tumor compared with normal, healthy tissue.
Gregory teaches that (§SYNTHETIC mRNAs ¶1) synthetic mRNAs are another approach for upregulating a tumor suppressor gene in cancer and that synthetic mRNAs are synthesized to mimic natural mRNAs and are translated in the cytoplasm to produce protein, which is indistinguishable to that resulting from the translation of endogenous mRNA. Gregory teaches that (§SYNTHETIC mRNAs-Using synthetic mRNAs to upregulate TSGs in cancer entire § and sub§s) such gene replacement system has already been successful in treating melanoma by replacing a different gene that is downregulated. Gregory teaches that in the case of PTEN, PTEN mRNA-containing nanoparticles were injected and increased T-cell infiltration, which helped reverse the immunosuppressive TME. Gregory teaches cationic liposomes encoding a different gene were used to treat another melanoma model.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of reducing melanoma tumor growth or slowing growth of melanoma cells in vivo by administering a vector encoding Gal-3 of Hayashi and Brown with the gene therapy methods of Gregory for the benefit of treating melanoma by administering a nucleic acid encoding Gal-3 without having to modify melanoma cells. One would have been motivated to do so with a reasonable expectation of success because Gregory teaches it was common in the art to treat cancer—including melanoma specifically—by administering a gene that is dysregulated in cancer and that synthetic mRNAs are … indistinguishable to that resulting from the translation of endogenous mRNA. One would have been motivated because injecting the nucleic acid without modifying cells would have been easier than modifying cells. One would have been motivated to do so with a reasonable expectation of success because Hayashi showed that overexpressing mouse Gal-3 reduced metastasis associated with melanoma, because Brown showed that Gal-3 expression correlates with melanoma-specific survival, and it would have been obvious to use the methods of Hayashi and Brown to reduce metastasis associated with melanoma in humans. It would have been obvious to an artisan to simply inject a nucleic acid sequence or vector encoding a nucleic acid sequence directly to the tumor or into a subject’s vein because of the teachings of Hayashi, Brown, and Gregory. Modifying the method of reducing melanoma metastasis (and therefore reducing tumor growth), slowing melanoma growth in vivo, and reducing metastasis of Hayashi and Brown with the gene therapy methods of Gregory would have produced methods with some of the limitations of Claims 1, 11, and 15.
Although Hayashi, Brown, and Gregory make obvious a method for reducing melanoma metastasis wherein the metastasis is, broadly speaking, under the skin (and can, therefore, be considered subcutaneous melanoma in its broadest sense), they do not explicitly teach reducing melanoma metastasis wherein the melanoma is located in subcutaneous tissues.
However, Mozzillo teaches (¶1) melanoma commonly produces cutaneous and subcutaneous metastases and commonly metastasizes to distant subcutaneous tissue.
It would have been obvious to an ordinarily skilled artisan before the effective filing date of the claimed invention to use the method of Hayashi, Brown, and Gregory with the teachings of Mozzillo for the benefit of reducing subcutaneous melanoma in a subject. One would have been motivated to do so with a reasonable expectation of success because Hayashi teaches expressing Gal-3 in melanoma cells reduces tumor growth and Mozzillo teaches melanoma commonly produces subcutaneous metastases. Since Hayashi demonstrates their method works to reduce lung metastases, an artisan would reasonably expect that the method of Hayashi, Brown, and Gregory would have the same effect on any melanoma or melanoma metastasis, including the subcutaneous melanoma metastases of Mozzillo.
Hayashi, Brown, Gregory, and Mozzillo do not explicitly teach measuring melanoma tumor volume over time (Claims 1 and 15) or measuring the number and size of colonies formed by melanoma cells (Claim 11).
However, Goldmacher, drawn to using tumor volumetrics to assess response to therapy in anticancer clinical trials, teaches (§Abstract) measuring entire tumour volumes to overcome some of the limitations of linear tumour measurements and to reliably improve detection of small changes and increase statistical power per subject in a trial. Goldmacher teaches (§The advantages of volumetric assessment ¶1) volumetric assessment of tumor size produces more accurate measurement and tracking and (§Precision of volume measurements ¶6) appropriately selected image acquisition and reconstruction parameters can lead to highly accurate and precise measurements. Altogether Goldmacher teaches that volumetric measurements of tumor size within a body provide the most accurate data on response to treatment.
Baraldi, drawn to growth and form of melanoma cell colonies, teaches (§1. Introduction ¶2) it is common in the art to count the number of colony-forming clones but that cancer cell colony growth experiments provide a wealth of other useful information such as colony size and shapes. Baraldi teaches (§1. Introduction ¶1) data about colony formation have a use in drug testing, wherein one compares how cell colonies form with or without a drug.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of reducing melanoma tumor growth and slowing growth of melanoma cells in a subject by administering a vector encoding Gal-3 of Hayashi, Brown, Gregory, and Mozzillo with the teachings about measuring tumor volume over time of Goldmacher and the teachings about measuring number and size of melanoma cell colonies of Baraldi for the benefit of tracking melanoma response to the Gal-3 expression. One would have been motivated to measure tumor volume over time with a reasonable expectation of success because Goldmacher teaches (§Abstract) tracking cancer tumor volume is a good way to measure response to a treatment in clinical trials, imaging techniques for doing so exist, and such measurements increase statistical power per subject. One would have been motivated to measure the number and size of melanoma cell colonies in vivo with a reasonable expectation of success because Baraldi teaches that (§1. Introduction ¶1-2) such measurements are commonly performed in the art, including to determine response to a treatment and (§1. Introduction ¶3) to study the cellular arrangement within a tumor. Modifying Hayashi, Brown, Gregory, and Mozzillo’s method of reducing melanoma tumor growth and slowing growth of melanoma cells in a subject by administering a vector encoding Gal-3 with Goldmacher’s teachings about measuring tumor volume over time of Goldmacher and Baraldi’s teachings about measuring number and size of melanoma cell colonies would have produced a method of reducing melanoma tumor growth in a subject comprising administering to the subject a pharmaceutical composition comprising a vector comprising a nucleic acid sequence that encodes Gal-3, and measuring melanoma tumor volume over time (most limitations of Claim 1 and some limitations of Claim 15) and method for slowing the growth of melanoma cells in vivo, the method comprising contacting the melanoma cells with a composition comprising nucleic acid or a vector comprising a nucleic acid sequence that encodes Gal-3, and measuring the number and size of colonies formed by the melanoma cells (most limitations of Claim 11).
Regarding Claims 2 and 18: Since Hayashi taught injection to the tail vein, which is parenteral administration, modifying the method of Hayashi and Gregory would have produced the method comprising most limitations of Claim 2 (and some limitations of Claim 18).
Regarding Claim 3: Since Hayashi teaches (§Discussion, final ¶) the function of Gal-3 in cancer cell metastasis is conserved in humans, a lower level of Gal-3 expression in human melanoma was found in metastatic relative to primary lesions, and induction of intracellular Gal-3 in cancer cells would be required to inhibit tumor metastasis in cancer therapy, it is clear that Hayashi intends for their method to be used on humans. Therefore most of the limitations of Claim 3 would have been obvious in view of Hayashi, Brown, Gregory, Goldmacher, and Baraldi.
Regarding Claims 4-5 and 12: Since the cells used by Hayashi were metastatic melanoma cells and NCI teaches that metastatic cancer is considered stage IV, and since Brown teaches nuclear expression of Gal-3 decreases with cancer stage, particularly wherein melanoma cells at stages 2-4 exhibit reduced Gal-3 expression, the method of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, and Baraldi would have produced most of the limitations of Claim 4. Since Hayashi used metastatic melanoma cells, the method of Hayashi Brown, Gregory, Mozzillo, Goldmacher, and Baraldi would have produced the method comprising most limitations of Claim 5 (and some limitations of Claim 12).
Hayashi Brown, Gregory, Mozzillo, Goldmacher, and Baraldi do not teach the method for reducing subcutaneous melanoma tumor growth in a subject, wherein the method includes the step of measuring expression levels of NFAT1 (a.k.a. NFATc2) in melanoma cells from the subject.
Regarding measuring expression of NFAT, Zhang teaches that NFAT1 expression correlates with melanoma stage and metastatic potential. Zhang is drawn to redox signals at the ER–mitochondria interface that control melanoma progression. Zhang teaches (§Abstract) we identified NFAT1-positive and NFAT1-negative melanoma subgroups, wherein NFAT1 expression correlates with melanoma stage and metastatic potential. Integrative bioinformatics … indicated that NFAT1 [is] associated with poor disease outcome. Zhang teaches (§NFAT1 regulates tumor-associated genes and along with TMXs affects disease outcome ¶1) we analyzed the relationship between [NFAT and other gene] individual expression levels and disease outcome in patients with cutaneous melanoma … Our analyses showed that patients with increased… NFAT1 expression had significantly lower survival expectancy.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods for reducing subcutaneous melanoma tumor growth in a subject of Hayashi Brown, Gregory, Mozzillo, Goldmacher, and Baraldi with the teachings about NFAT1 expression of Zhang for the benefit of determining patient prognosis. One would have been motivated to do so with a reasonable expectation of success because Zhang teaches there is a relationship between NFAT1 expression and disease outcome, and an artisan treating a patient would have wanted to be able to 1) modify a treatment plan based on likely disease outcome (i.e., to adjust treatment dose to avoid over- or under-treating melanoma) and 2) keep their patient well informed about potential outcomes so the patient could make an informed decision when choosing a treatment plan. One would have been motivated to do so with a reasonable expectation of success because the teachings of Zhang indicates it is common in the art to profile expression in melanoma cells to predict disease severity and teach a predictive relationship between NFAT1 expression and melanoma metastasis. An artisan would have wanted to know whether expressing Gal-3 in melanoma cells affected expression of prognostic genes for the benefit of helping patients make decisions about further treatment. Therefore, all the limitations of Claims 1-5 (and some limitations of Claims 11-12, 15, and 18) would have been obvious in view of Hayashi Brown, Gregory, Mozzillo, Goldmacher, Baraldi, and Zhang.
Claims 1-9, 11-12, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, and Zhang, as applied to claims 1-5 above, and further in view of Lin (of record), and Dimitrakopoulou (2019. Monitoring of patients with metastatic melanoma treated with immune checkpoint inhibitors using PET–CT. Canc. Immunol. Immunother. 68:813-822, “Dimitrakopoulou”, of record). This rejection has been updated in response to the claim amendments.
The teachings of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, and Zhang as applicable to Claims 1-5 have been described above. The teachings of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, and Zhang as applicable to some of the limitations of Claims 11-12, 15, and 18 have been described above.
Hayashi, Brown, Gregory, Mozzillo, Goldmacher, and Baraldi, and Zhang, teach a method that reduces melanoma tumor growth (by reducing metastasis) in a subject, slows growth of melanoma cells in vivo (by reducing number of metastatic foci, total cell growth over time is reduced), and inhibits or slows melanoma metastasis, the method comprising administering a pharmaceutical composition comprising a nucleic acid encoding Gal-3, measuring tumor volume over time or the method comprising measuring the number and size of colonies formed by the melanoma cells, and measuring levels of NFAT1 expression in melanoma cells from the subject.
Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, and Zhang do not teach that the melanoma has been treated with immune checkpoint inhibitor (ICI) therapy or is resistant to ICI therapy (i.e., Claims 6-9, 11-12, 14, 16-17, or 19) or that the subject has been treated with an ICI therapy wherein the ICI therapy is an anti-CTLA-4 antibody (Claims 8 or 14) or that the ICI therapy is an anti-PD-1 therapy (Claim 9).
However, Lin teaches that gene therapy can confer sensitivity to anti-PD-1 in a mouse model of melanoma. Lin is drawn to reactivating the tumor suppressor PTEN using mRNA nanoparticles to enhance antitumor immunity. Lin teaches (§Antitumor immune responses are induced by mPTEN@NPs in vivo; Fig. 3A-B) nanoparticles that deliver PTEN mRNA induce anti-tumor responses in PTEN-mutated melanoma-bearing mice. Lin teaches (§mPTEN@NPs confer sensitivity to anti–PD-1 in an orthotopic mouse model of Pten-null prostate cancer ¶1) delivering PTEN mRNA to tumors wherein PTEN is mutated can re-sensitize the tumor to ICI therapy. Lin teaches that (§mPTEN@NPs improve the antitumor efficacy of anti–PD-1 in a subcutaneous mouse model of Pten-mutated melanoma; Fig. 4A-C) loss of PTEN leads to a poor response to anti-PD-1 therapy in patients with melanoma but restoring PTEN using gene therapy delivering PTEN mRNA restored the therapeutic effect of anti-PD-1 in a PTEN-mutated melanoma model. Lin teaches that the combination of PTEN mRNA + anti-PD-1 achieved greater antitumor efficacy after three cycles of treatment, in comparison to either mPTEN@NPs (P < 0.05) or anti–PD-1 alone (P < 0.01) (Fig. 4, B and C). An excerpt of Fig. 4 is shown here:
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Figure 4A shows that the PTEN-encoding nucleic acids were administered prior to and after the administration of the ICI therapy, which is a limitation of Claim 19.
Although Lin teaches a gene therapy delivering PTEN mRNA and the instant claims recite a gene therapy delivering a nucleic acid encoding Gal-3, the teachings of Lin would have taught an artisan that restoring a gene that is deficient or down-regulated in melanoma and adding an immune checkpoint inhibitor therapy (ICI) such as anti-PD-1 therapy has the potential to restore cancer sensitivity to the ICI (in the case of Lin, the anti-PD-1 therapy). Therefore it would have been obvious to an artisan to use the method for treating melanoma of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, and Zhang with anti-PD-1 therapy to treat anti-PD-1-resistant melanoma.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating melanoma, and slowing melanoma growth by reducing metastasis by administering a composition comprising a nucleic acid sequence encoding Gal-3 of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Mozzillo, Baraldi, and Zhang with the antiPD-1 therapy and teachings of Lin for the benefit of treating melanoma that is resistant to ICI therapy. One would have been motivated to do so with a reasonable expectation of success because Lin teaches that a gene therapy for treating melanoma can re-sensitize ICI-resistant melanoma cells to the ICI. Modifying the method of treating melanoma, slowing melanoma growth in vivo, and reducing metastasis by administering a composition comprising a nucleic acid sequence encoding Gal-3 of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, and Zhang with the antiPD-1 therapy and teachings of Lin would have produced a method with the limitations of Claims 6-7, 9, and 11-12 (and some limitations of Claims 16-17). Lin teaches that their Figure 4A shows that the downregulated gene-encoding nucleic acids were administered prior to and after the administration of the ICI therapy, so it would have been obvious to an artisan to administer the Gal-3-encoding nucleic acids prior to and after the administration of the ICI therapy. Doing so would have produced some of the limitations of Claim 19.
Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, and Lin do not teach that the ICI is an antibody to CTLA-4 (Claims 8 and 14).
Regarding Claims 8 and 14: However, Dimitrakopoulou, drawn to monitoring patients with metastatic melanoma, teaches (§Introduction-Immunotherapy ¶1) ICIs such as ipilimumab, a CTLA-4 inhibitor antibody and anti-PD-1 inhibitor antibodies can improve melanoma control, including progression-free survival and overall survival. However, Dimitrakopoulou teaches (same §) resistance to these therapies, particularly after the initial response, limits their long-term effects.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating melanoma, and slowing melanoma growth by reducing metastasis by administering a composition comprising a nucleic acid sequence encoding Gal-3 and administering an antibody to PD-1 wherein the melanoma cells are resistant to the ICI is anti-PD-1 of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, and Lin with the anti-CTLA-4 therapy and teachings of Lin and Dimitrakopoulou for the benefit of treating melanoma that is resistant to ICI therapy wherein the ICI therapy is anti-CTLA-4. One would have been motivated to do so with a reasonable expectation of success because Lin teaches that a gene therapy for treating melanoma can re-sensitize ICI-resistant melanoma cells to the ICI wherein the ICI therapy is anti-PD-1 and Dimitrakopoulou teaches melanoma can also become resistant to the ICI anti-CTLA-4. It would have been obvious to try Lin’s strategy of administering a gene therapy to express a gene that is downregulated in the melanoma cells + the ICI to which the melanoma cells are resistant wherein the gene therapy expresses Gal-3 and the ICI that is administered is anti-CTLA-4. The combination of administering a nucleic acid expressing Gal-3 and an anti-CTLA-4 antibody would have been a minor modification to the strategy of Hayashi, Brown, Gregory, Goldmacher, Baraldi, Zhang, and Lin and would have been obvious because Dimitrakopoulou teaches that melanoma can also become resistant to the ICI anti-CTLA-4. Modifying the method of treating melanoma, slowing melanoma growth in vivo, and reducing metastasis by administering a composition comprising a nucleic acid sequence encoding Gal-3 and administering an anti-PD-1 ICI therapy of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, and Lin with the anti-CTLA-4 therapy of Dimitrakopoulou and teachings of Lin would have produced a method with the limitations of Claims 8 and 14 (and some limitations of Claims 16-17).
Claims 1-9, 11-12, 14-19, 21, and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, and Dimitrakopoulou as applied to claims 1-9, 11-12, and 14 above, and further in view of More (et al. 2016. Galectin-3-induced cell spreading and motility relies on distinct signaling mechanisms compared to fibronectin. Mol. Cell Biochem. 416:179-191, “More”, of record) as evidenced by Wikipedia (Archived 18 September 2023. “Extracellular signal-regulated kinases”. Available online at Wikipedia.org. Accessed on 05 May 2025, “Wikipedia”, of record), Nunomura (et al. 2022. Interleukin-1β triggers matrix metalloprotease-3 expression through p65/RelA activation in melanoma cells. PLoS ONE 17[11]:e0278220, “Nunomura”, of record), Filimon (et al. 2021. Interleukin-8 in Melanoma Pathogenesis, Prognosis and Therapy—An Integrated View into Other Neoplasms and Chemokine Networks. Cells 11[1]:120, “Filimon”, of record), Chien (et al. 2009. Activated Wnt/ß-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model. PNAS 106[4]:1193-1198, “Chien”, of record), Ross (and Wilson. 1998. Expression of c-Myc oncoprotein represents a new prognostic marker in cutaneous melanoma. Br. J. Surg. 85:46-51, “Ross”, of record), Nagasaka (et al. 1999. Cyclin D1 Overexpression in Spitz Nevi: An Immunohistochemical Study. Am. J. Dermatopathol. 21[2]:115-120 ABSTRACT ONLY, “Nagasaka”, of record), Li (et al. 2019. Glypican 6 is a putative biomarker for metastatic progression of cutaneous melanoma. PLoS ONE 14[6]:e0218067, “Li”, of record), International Publication Number WO2008/069881 (published on 12 June 2008, “WO881”, of record), Markman (2022. Metastatic melanoma. City of Hope. Available online at cancercenter.com. Accessed on 23 October 2025, “Markman”, of record), Alizadeh (et al. 2003. Reduction of Liver Metastasis of Intraocular Melanoma by Interferon-β Gene Transfer. Immunol Microbiol. 44:3042-3051, “Alizadeh”), and Galecto (of record). This rejection has been updated in response to the claim amendments.
The teachings of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, and Dimitrakopoulou as applicable to Claims 1-9, 11-12, and 14 and some limitations of Claims 15-19 have been described above.
Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, and Dimitrakopoulou teach a method of reducing melanoma tumor growth (by reducing metastasis) in a subject, slowing growth of melanoma cells in vivo (by reducing number of metastatic foci, total cell growth over time is reduced), and inhibiting or slowing melanoma metastasis, the method comprising administering a pharmaceutical composition comprising a nucleic acid encoding Gal-3 and measuring tumor volume over time or the method comprising measuring the number and size of colonies formed by the melanoma cells and measuring NFAT1 expression levels in melanoma cells from the subject, and wherein the subject has been treated with an ICI therapy for melanoma or wherein the melanoma is ICI-resistant.
Hayashi, Brown, Gregory, Goldmacher, Baraldi, Zhang, Lin, and Dimitrakopoulou do not teach the method also includes measuring phosphorylation levels of ERK1/2 and AKT in melanoma cells from the subject, or measuring expression levels of MMP-3, IL-8, β-catenin, c-Myc, cyclin D1, or GPC6 in melanoma cells from the subject (Claims 15-19 and 21).
However, measuring a variety of biomarkers including all those recited in Claim 15 (and claims depending therefrom) would have been obvious while treating melanoma based on the teachings of the prior art.
More, drawn to Gal-3-induced cell spreading and motility, teaches (§Abstract) secreted Gal-3 is incorporated into the extracellular matrix (ECM) and utilized by cancer cells for spreading and metastatic dissemination. More teaches (same §; §Introduction ¶5) Akt and Erk regulate actin dynamics. Artisans know that dynamic actin filaments are involved in cell motility which is a component of metastasis. More teaches (§Introduction ¶3) secreted extracellular Gal-3 can affect motility-related processes but it is not clear how immobilized [Gal]-3 as a component of ECM/BM promotes such complex cellular processes like spreading and movement critical for cancer cell metastasis. More teaches (§Results-B16F10 melanoma cells show distinct cytoskeletal organization when allowed to spread on galectin-3 as opposed to fibronectin and §Spreading kinetics of B16F10 melanoma cells on galectin-3 is more dynamic) actin cytoskeleton organization differs depending on the kind of substrate melanoma cells are spreading on. More teaches (§Akt phosphorylation is inversely regulated in cells spread on galectin-3 and fibronectin while Erk is regulated similarly in both, Figs. 5-6) different patterns of cell migration are regulated by Akt and/or Erk pathways. More teaches that (same §, ¶1) Akt phosphorylation increases with time in cells plated on Gal-3 but decreases when cells are plated on fibronectin, and Erk phosphorylation decreases in cells plated on either Gal-3 or fibronectin. Those results indicate that extent of Akt and Erk phosphorylation reveal information about the content of the ECM: an ECM containing more Gal-3 leads to increased Akt phosphorylation and reduced Erk phosphorylation whereas an ECM containing more fibronectin leads to reduced Akt phosphorylation and reduced Erk phosphorylation. More teaches (§Discussion, second-to-last ¶) their studies demonstrate that Gal-3 supports spreading and movement of cells whose characteristics are different from the spreading and movement that occurs on fibronectin. More teaches (§Discussion, final) Gal-3 expressed on the lungs is utilized by melanoma cells for random movement and establishment of metastatic foci.
Wikipedia teaches that (§Mitogen-activated protein kinase 3 and §Mitogen-activated protein kinase 1) Erk1 and Erk2 respectively correspond with MAPK3 and MAPK1. More refers to (§Introduction ¶5; § Akt phosphorylation is inversely regulated in cells spread on galectin-3 and fibronectin while Erk is regulated similarly in both ¶1) the Erk-MAPK cascade. That makes it clear that More’s “Erk-MAPK pathways” are talking about Erk1/2.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of reducing melanoma tumor growth in a subject, slowing growth of melanoma cells in vivo, and/or inhibiting or slowing melanoma metastasis, the method comprising administering a pharmaceutical composition comprising a nucleic acid encoding Gal-3 of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, and Dimitrakopoulou with the teachings about measuring extent of Akt and Erk phosphorylation of More for the benefit of gaining insight into the ECM and melanoma cells’ metastatic potential. One would have been motivated to do so with a reasonable expectation of success because More teaches that (§Discussion, final ¶) more Gal-3 in the ECM relates to the establishment by melanoma of metastatic foci and that increased levels of Akt phosphorylation and decreased levels of Erk phosphorylation indicate a greater extent of Gal-3 in the ECM. Therefore measuring the extent of Akt and Erk phosphorylation would provide insight into the presence of Gal-3 in the ECM, with presence of more Akt phosphorylation and less Erk phosphorylation indicating higher Gal-3 which corresponds to greater metastatic potential.
Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, Dimitrakopoulou, and More do not teach measuring expression levels of MMP-3, IL-8, β-catenin, c-Myc, cyclin D1, or GPC6 in melanoma cells from the subject (further limitations of Claim 15). Note that expression levels can refer to levels of either RNA or protein expression and the claim is interpreted as encompassing either or both RNA and protein expressions. The references do not explicitly teach treating liver metastasis.
Nunomura, drawn to MMP3 expression in melanoma cells, teaches (§Discussion ¶2) high expression levels of MMP-3 in human patients have been reported to be correlated with shorter disease-free survival in human metastatic melanoma and MMP-3 protein expression and release in human melanoma have been observed in aggressive and highly metastatic cell lines.
Filimon, drawn to IL-8 in melanoma pathogenesis and prognosis, teaches (§3.3.1. Tumor Cells and Immune Cells: IL-8 and Melanoma cells) the expression of steady state levels of IL-8 mRNA in melanoma cells correlated with their metastatic capacity and that no IL-8 mRNA was observed in non-tumorigenic, non-metastatic ones cells. Filimon teaches that IL-8 expression was highly increased in metastatic specimens.
Chien, drawn to β-catenin signaling in melanoma, teaches (§Results-Nuclear ß-Catenin Levels Correlate with Improved Patient Survival) nuclear β-catenin levels correlate with improved patient survival and melanoma progression is associated with a loss of Wnt/β-catenin signaling.
Ross, drawn to expression of c-Myc in melanoma, teaches (§Abstract-Results) high expression of c-Myc predicted poor outcome in both primary and metastatic disease and c-Myc expression was able to discriminate prognosis in thick melanoma lesions.
Nagasaka, drawn to cyclin D1 overexpression in Spitz nevi, teaches (§Abstract) cyclin D1 is overexpressed in malignant melanomas.
Li, drawn to glypican 6 (GPC6) as a putative biomarker for metastatic progression of cutaneous melanoma, teaches (§Abstract) their results indicate that GPC6 functions in tumor metastatic progression and GPC6 expression is an early biomarker for melanoma metastatic progression.
WO881 teaches method for determining a profile data set for a subject with skin cancer based on a sample from the subject, wherein the sample provides a source of RNAs. WO881 teaches (p. 20 L14-20) the sample can be a cell or multiple cells and (p. 37 L9-15) a sample can be any tissue or cell (including a circulating tumor cell), thereby encompassing tumor cells. WO881 teaches (p. 22 L20-27) the gene expression profile called the Precision Profile™ for Melanoma Cancer includes one or more genes listed in Table 1, whose expression is associated with skin cancer. WO881 teaches (p. 22 L4-16) their gene expression profiles may be used for measuring therapeutic efficacy of treatment compositions and (p. 25 L4-10) assessing prognosis. WO881 teaches their methods of diagnosis or prognosis of skin cancer includes (p. 6 L10-14) measuring expression of at least one of any of the skin cancer associated genes listed in Tables 1-6. Examination of those tables indicates that MMP3, IL-8, and β-catenin are listed in Table 1, the Precision Profile ™ for Melanoma.
Markman teaches (§What is metastatic melanoma?) the liver is a common melanoma metastasis site. Markman teaches (§Metastatic melanoma symptoms) if melanoma spreads to the liver it can cause loss of appetite, fatigue, swelling, jaundice, and itchiness.
Alizadeh teaches (§Abstract; § Effect of IV Transfer with AdCMVIFN-β on Liver Metastasis of Intraocular Melanoma) adenovirus-mediated transfer of mouse interferon-β (AdCMVIFN-β) via intravenous treatment resulted in an 86% reduction in the number of metastatic foci in the liver compared with mice treated with control (AdCMVLacZ). Alizadeh teaches (§Abstract-Results) it was the gene transfer that led to the outcome. Alizadeh teaches (§Main text ¶4) adenovirus vectors have a predilection for transferring genes to the liver after IV injection. Altogether, Alizadeh shows it is possible to deliver a gene therapy to melanoma metastasis in the liver.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating melanoma of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, Dimitrakopoulou, and More with the teachings about the relationship between increased NFAT1 and poor disease outcome of Zhang, the teachings about high MMP3 expression correlating with shorter disease-free survival and highly aggressive and metastatic melanoma cells of Nunomura, the teachings about higher expression levels of IL-8 mRNA correlating with melanoma cell metastatic capacity of Filimon, the teachings about increased nuclear β-catenin correlating with improved patient survival of Chien, the teachings about increased c-Myc expression predicting poor outcome of Ross, the teachings about cyclin D1 overexpression occurring in malignant melanoma of Nagasaka, the teachings about high GPC6 expression occurring in metastatic melanoma of Li, the teachings about measuring mRNAs to predict outcomes of melanoma of WO881 for the benefit of gathering information about patient prognosis, the teachings about the liver being a common melanoma metastasis site of Markman, and the teachings about using adenovirus to deliver a gene to treat melanoma metastasis in the liver of Alizadeh. One would have been motivated to do so with a reasonable expectation of success because each reference teaches there is a relationship between gene or protein expression and disease outcome, and an artisan treating a patient would have wanted to be able to 1) modify a treatment plan based on likely disease outcome (i.e., to adjust treatment dose to avoid over- or under-treating melanoma) and 2) keep their patient well informed about potential outcomes so the patient could make an informed decision when choosing a treatment plan. One would have been motivated to do so with a reasonable expectation of success because WO881 teaches it is common in the art to profile RNA expression in melanoma cells to predict disease severity and because all of the cited references teach a predictive relationship between gene or protein expression and melanoma outcome. An artisan would have wanted to know whether expressing Gal-3 in melanoma cells affected expression of prognostic genes for the benefit of helping patients make decisions about further treatment.
An artisan would have wanted to use the method of treating melanoma or inhibiting melanoma metastasis of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, Dimitrakopoulou, and More with the teachings about melanoma commonly metastasizing to the liver for the benefit of slowing melanoma metastasis at a site where it can cause further unpleasant symptoms. An artisan would have wanted to use the adenovirus of Alizadeh to deliver the Gal-3 because the reference teaches adenovirus vectors are good for transferring genes to the liver and shows expressing a different gene to treat melanoma metastasis to the liver. Such application would have been obvious to try because of the recognized need to treat liver metastasis and Hayashi teaches expressing Gal-3 improves metastasis. Successful slowing of liver metastasis would have been a reasonable expectation because Hayashi showed expressing Gal-3 in melanoma cells slows metastasis in the lungs. Since Hayashi describes (§Tumor Cell Metastasis is Affected by Gal-3 in Human Melanoma Cells) teaches expressing Gal-3 reduces metastatic potential via a general mechanism (i.e., reducing integrin), an artisan would have expected metastasis to any organ—including the liver—to be slowed, suppressed, or inhibited, particularly when using Alizadeh’s adenovirus and methods shown to slow melanoma metastasis in the liver and in view of Alizadeh’s teaching that adenovirus vectors have a predilection for transferring genes to the liver.
Modifying the method of treating melanoma or inhibiting melanoma metastasis of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, Dimitrakopoulou, and More with the teachings about the relationship between gene/protein expression and disease outcome of Zhang, Nunomura, Filimon, Chien, Ross, Nagasaka, Li, WO881, Markman, and Alizadeh would have produced all the limitations of Claims 15-19 besides the Gal-3 inhibitor.
The teachings of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, Dimitrakopoulou, More, Nunomura, Filimon, Chien, Ross, Nagasaka, Li, WO881, Markman, and Alizadeh as applicable to Claims 1, 11, and 15 have been described.
Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, Dimitrakopoulou, More, Nunomura, Filimon, Chien, Ross, Nagasaka, Li, WO881, Markman, and Alizadeh teach a method that reduces melanoma tumor growth (by reducing metastasis) in a subject, slows growth of melanoma cells in vivo, and inhibits or slows melanoma metastasis (including liver metastasis), the method comprising administering a pharmaceutical composition comprising a nucleic acid encoding Gal-3 and measuring tumor volume over time or the method comprising measuring the number and size of colonies formed by the melanoma cells, and measuring phosphorylation status of ERK1/2 and AKT, as well as measuring expression of a slew of known melanoma related genes and proteins.
Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, Dimitrakopoulou, More, Nunomura, Filimon, Chien, Ross, Nagasaka, Li, WO881, Markman, and Alizadeh do not teach that the method further comprises administering an inhibitor of Gal-3 (Claims 15-19) or the specific inhibitor GB1211 (Claims 21 or 23-24).
However Galecto teaches using the Gal-3 inhibitor GB1211 in combination with Pembrolizumab in patients with metastatic melanoma. Galecto is drawn to a press release about their upcoming clinical trial. Galecto teaches that Gal-3 is linked to metastatic potential including in melanoma because it prevents checkpoint inhibitors from binding to their targets:
(¶2) Galectin-3 is overexpressed in many cancers, including melanoma and head and neck squamous cell carcinoma (HNSCC). Increased galectin-3 expression in tumors is linked to tumor growth, invasiveness, and metastatic potential. Furthermore, increased levels of galectin-3 in the tumor microenvironment can cause checkpoint inhibitor resistance by blocking the binding of the checkpoint inhibitor antibodies, pembrolizumab and atezolizumab (Tecentriq®), to their respective targets. Preclinical data has shown that GB1211 has the ability to reduce galectin-3-induced checkpoint inhibitor blockages, thus preventing galectin-3 from inducing checkpoint inhibitor resistance.
That indicates that GB1211 works to treat melanoma by blocking Gal-3 so it cannot impede ICI function.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of treating melanoma by expressing Gal-3 and using a PD-1 inhibitor and measuring melanoma-related gene expression of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, Dimitrakopoulou, More, Nunomura, Filimon, Chien, Ross, Nagasaka, Li, WO881, Markman, and Alizadeh with the melanoma treatment including GB1211 of Galecto for the benefit of stopping extracellular Gal-3 from blocking the binding of the checkpoint inhibitor antibodies to their respective targets thereby improving efficacy of melanoma treatment. One would have been motivated to do so with a reasonable expectation of success because Galecto teaches that (¶4) galectin inhibition can be used to enhance tumor treatment and this new trial is an important step forward in expanding the reach of GB1211 into additional cancer indications, addressing the unmet needs in the treatment of metastatic melanoma. One would have been motivated to do so because Hayashi teaches that although they found that intracellular Gal-3 regulates metastatic potential, the role of extracellular Gal-3 in metastasis merits further study: (§Lack of Gal-3 Expression in Tumor Cells Themselves Enhances Metastatic Colony Formation ¶2) the possibility that secreted Gal-3 does have an influence on tumor metastasis cannot be excluded, but the results suggest the notion that metastatic potential is mostly regulated by intracellular Gal-3. Additionally Hayashi teaches that (§Discussion ¶2) the same molecule can affect processes of cancer biology in a context-dependent manner. An artisan would have realized that the method of treating melanoma of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, Dimitrakopoulou, More, Nunomura, Filimon, Chien, Ross, Nagasaka, Li, WO881, Markman, and Alizadeh could be further improved by administering the GB1211 of Galecto since Galecto demonstrated how galectin inhibition can be used to enhance tumor treatment including for melanoma specifically. Since Hayashi teaches that induction of intracellular Gal-3 in cancer cells would be required to inhibit tumor metastasis in cancer therapy and Galecto teaches that GB1211 works via a different mechanism, namely inhibiting Gal-3 from blocking binding of antibody ICIs to their target—which an artisan would have realized occurs in the extracellular environment—an artisan would have recognized that each kind of treatment (i.e., overexpressing Gal-3 inside of cells with the nucleic acid encoding Gal-3 or inhibiting extracellular Gal-3 by administering GB1211) operates on Gal-3 via a different mechanism but that both treatments could help treat melanoma. Furthermore, More teaches that metastatic melanoma binds and metastasizes by binding to extracellular Gal-3 in the ECM, so an artisan would have readily realized that inhibiting extracellular Gal-3 with GB1211 would prevent melanoma from metastasizing because GB1211 would prevent cells from binding to extracellular Gal-3 and using it as a ligand to move around. Modifying the method of treating melanoma by expressing Gal-3 and using a PD-1 inhibitor of Hayashi, Brown, Gregory, Mozzillo, Goldmacher, Baraldi, Zhang, Lin, Dimitrakopoulou, More, Nunomura, Filimon, Chien, Ross, Nagasaka, Li, WO881, Markman, and Alizadeh with the GB1211 (and pembrolizumab) of Galecto would have produced the methods of Claims 15-19, 21, and 23-24.
Response to Arguments
Applicant's arguments filed 24 January 2026 have been fully considered but they are not persuasive. Each rejection is discussed below. Arguments that are no longer relevant are not addressed.
112a scope of enablement
Applicant argues against the scope of enablement rejection on pp. 6-7. Applicant argues that the law requires that the scope of enablement provided by the Spec. bear a reasonable correlation to the scope of the claims and that compliance with the enablement requirement doesn’t turn on whether an example is disclosed, working example, or reduction to practice. Applicant argues that the Spec. includes multiple in vitro experiments involving manipulation of Gal-3 in melanoma cells and repeatedly describes Gal-3’s effects on melanoma cell proliferation, colony formation, invasion, and metastatic potential.
Applicant’s arguments discuss in vitro experiments involving manipulation of Gal-3 in melanoma cells. That general phrasing of “manipulation”—without discussing the specific type of manipulation—is noted.
Applicant argues that the Spec. teaches that loss of Gal-3 results in a significantly increased number and size of melanoma colonies in vitro and points to Figures 3F and 3G. Applicant argues that:
[those] data demonstrate that Gal-3 functions as a negative regulator of melanoma cell growth in vitro and that a skilled artisan would reasonably understand that increasing Gal-3 levels, for example, by introducing Gal-3-encoding nucleic acids into melanoma cells, as taught in the specification, would produce the opposite effect, namely suppression or slowing of melanoma cell growth invitro. Such reasoning reflects standard scientific principles routinely applied by skilled artisans and does not amount to undue experimentation.
Applicant then argues that Hayashi et al. conclude that Gal-3 overexpression increased melanoma cell number in vitro while reducing metastasis in vivo and states: However, the present specification reports contrary in vitro results, showing that absence of Gal-3 increases melanoma colony number and size.
Applicant’s argument that the present specification reports contrary in vitro results to Hayashi’s results showing that Gal-3 overexpression increased melanoma cell number in vitro is not persuasive. As acknowledged by Applicant, their results show only that absence of Gal-3 increases melanoma colony number and size. Applicant’s results cannot be considered “contrary” to Hayashi’s because Applicant did not measure the same thing as what Hayashi measured which is rate of in vitro cell growth (i.e., number of cells over time) of Gal-3–overexpressing metastatic melanoma cells in vitro (see Hayashi Figs. 7BC). Applicant measured only in vitro cell growth of metastatic melanoma cells wherein Gal-3 was knocked down, and never measured what happens to metastatic melanoma cell growth in vitro when Gal-3 is overexpressed.
As discussed in the rejection, although it is sometimes the case that a knockdown phenotype is the opposite of an overexpression phenotype, that is not always the case. In fact, it is well known in the art that a knockdown/knockout phenotype is not necessarily the opposite of the overexpression phenotype. For example, the rejection discusses that Prelich teaches (§Distinguishing the mechanisms-Determining the loss-of-function phenotype ¶1)
The primary test to distinguish the mechanism responsible for an overexpression phenotype is determining the loss-of-function phenotype of the gene of interest. Three outcomes can be envisioned: loss-of-function could cause either the opposite phenotype of overexpression, the same phenotype, or no phenotype. The simplest scenario to interpret is when overexpression and deletion cause opposite phenotypes…
That indicates that opposite phenotypes are “the simplest scenario”. But Prelich also teaches (same §, ¶2) in contrast with the previous examples, overexpression of the wild-type gene can also cause identical phenotypes as loss-of-function mutations. Prelich teaches another scenario (same §, ¶3) a final scenario is when a gene that causes an overexpression phenotype has no obvious deletion phenotype. All of the outcomes Prelich discusses start with knowing the overexpression phenotype, but a person of ordinary skill should understand how the exact same principles apply to a case when the knockdown phenotype is known and the overexpression phenotype is sought. That is why Prelich concludes (§Summary and Future Directions ¶1) with the general assessment that: A lesson emerging from systemic knockout studies is that loss-of-function mutations alone are insufficient to deduce gene functions. Those teachings indicate that it is not possible to predictably extrapolate an overexpression phenotype from a knockdown/knockout phenotype. Evidence must be presented because outcomes are unpredictable.
Altogether, Applicant’s arguments are not persuasive because the art discloses what happens to metastatic melanoma cell growth in vitro when Gal-3 is overexpressed: growth increases. That outcome is a fact because Hayashi shows it in their data (Fig. 7BC). If Applicant has obtained a different result from what is in the art—and such a result is required by their claim (i.e., the recited outcome that Gal-3 overexpression slows metastatic melanoma cell growth in vitro)—they should provide data demonstrating that.
Contrary to their assertion, Applicant is not being required to present a working example for every claimed embodiment. They are only asked to present an example demonstrating their method works as claimed in this case because evidence in the art demonstrates that their claimed result is unpredictable.
Therefore the 112(a) scope of enablement rejection is maintained.
Applicant can overcome this rejection by presenting data showing that artificially expressing or overexpressing Gal-3 in melanoma cells slows their growth in vitro.
103 rejections
Applicant’s arguments (pp. 7-12) about the 103 rejection are not persuasive.
Applicant argues that (pp. 7-9) the applied references don’t teach the newly added limitation, the method step of measuring expression levels of NFAT1 in melanoma cells from the subject. That argument is no longer relevant because the rejection was amended (as necessitated by the claim amendments) to include a method step of measuring expression levels of NFAT1 in melanoma cells from the subject. Doing so would have been obvious because Zhang indicates that high NFAT1 levels are associated with poor prognosis, so an artisan would have wanted to measure NFAT1 levels so a patient would be able to make informed treatment decisions. Therefore the arguments on pp. 7-9 are not found persuasive.
Then Applicant argues that (pp. 9-12) an artisan would not reasonably extrapolate therapeutic efficacy from lung metastases to liver metastases. Applicant argues that simply knowing that the liver is a common site of melanoma metastasis does not provide a reasonable expectation of success that a given therapeutic approach—particularly one not shown to affect liver metastases—would inhibit or suppress melanoma growth in the liver. Applicant argues that the liver presents a highly specialized microenvironment which affects therapeutic responsiveness. Applicant presents the art of Conway because it teaches that liver melanoma metastases have significantly reduced immune infiltrate than lung metastases. Applicant argues that there wouldn’t have been a motivation to combine Hayashi with the other references and that there wouldn’t have been any reasonable expectation of success of doing so. Applicant mentions that is especially the case in view of the contradictory results between Hayashi and what’s shown in the Spec.
First of all, a person of ordinary skill in the art wouldn’t have had access to the Spec. when planning their experiments or designing a method of treatment because the 103 rejection is based on what an artisan would have known before the Spec. was filed. Secondly, even if they had somehow had access to Applicant’s results, what is in the Spec. wouldn’t have had any influence on what the artisan would have done regarding expressing Gal-3 to treat melanoma. That is because, as discussed above in arguments about 112a scope of enablement rejection, nothing in the Spec. actually shows what happens when Gal-3 is overexpressed, aside, of course, from Figs. 4C, 4I, and 8E. As discussed above, those figures show that overexpression of Gal-3 (1) suppresses pathways that are upregulated in Gal-3 KD experiments and (2) results in reduced NFAT1 expression. The experiments in the Spec. don’t show how Gal-3 overexpression affects melanoma cell growth or liver metastasis because, once again, they don’t measure or study those outcomes after overexpressing Gal-3.
In addition, it is notable that Applicant asserts that an artisan wouldn’t have had a reasonable expectation of success in producing the claimed outcomes of inhibiting, suppressing, or slowing liver metastasis since Applicant themselves have not any presented data of successfully producing those outcomes by overexpressing Gal-3. Regarding liver metastasis, Applicant presents only Figs. 7C and 7D. Both of those figures show only what happens when Gal-3 is knocked down. Based on what is presented, Applicant has the exact same expectation of success as what would have been obvious in view of the prior art.
Regarding Applicant’s comment about “contradictory results”, that is not persuasive because no contradictory results have been presented. The only data we have about the effects of overexpressing Gal-3 in melanoma cells are what Hayashi has presented; Applicant has shown nothing to “contradict” Hayashi’s results. Hayashi teaches overexpressing Gal-3 in melanoma reduces metastasis, which is, generally, what the instant claims recite. Applicant should present their data showing the allegedly “contradictory results”.
ATTORNEY ARGUMENTS CANNOT TAKE THE PLACE OF EVIDENCE
The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
See MPEP § 2145 generally for case law pertinent to the consideration of applicant’s rebuttal arguments.
MPEP §716.01(c)
Applicant is encouraged to present their data documenting their claimed outcomes.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., any amount of therapeutic responsiveness, any amount of immune infiltrate) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Then, on p. 12, Applicant argues that hindsight reasoning has been applied and quibbles about the number of references that have been applied.
In response to Applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this case, every piece of the claims was known in the prior art, as detailed in the rejection.
In response to Applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991). Regarding the number of references, a person of ordinary skill knows that it is routine and conventional in the art of designing biotechnological experiments and methods of treating a disease to apply knowledge gathered from tens, hundreds, or even thousands (or more) references. In this case, the claims in question recite many limitations that are a variety of known cancer-associated genes and proteins. Therefore it is entirely reasonable to use an assortment of references to demonstrate that all of those limitations were known. In addition, the claim limitations requiring numerous references are merely directed to “measuring” a selection of known factors and the cited art shows those factors were known and measuring them in cancer patients or cancer cells was known. The “measuring” is a method step that doesn’t affect the outcome.
Finally, the reference Alizadeh has been added to demonstrate that systemic injection of adenovirus vector results in target gene expression in melanoma metastases to the liver. That demonstrates that it was conventional to deliver a gene to melanoma metastasis in the liver. Given all that, there is no reason an artisan wouldn’t have had a reasonable expectation of success when applying the method that would have been obvious in view of the prior art.
Altogether, the 103 rejections are maintained.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Liu (et al. 2018. NFAT1 enhances the effects of tumor-associated macrophages on promoting malignant melanoma growth and metastasis. Biosci. Report. 38: BSR20181604, “Liu”) as evidenced by Grand (et al. 1935. Neoplasm Studies I. Cells of Melanoma in Tissue Culture. Am. J. Cancer 24[1]:36-50, “Grand”).
Liu teaches that (§Abstract) human malignant melanoma tissues exhibited increased CD68+ macrophage infiltration and NFAT1 expression compared with normal pigmented nevus tissues NFAT1 overexpression, and that NFAT1 overexpression in the TME promoted tumor growth and metastasis in vivo. Liu teaches (same §) NFAT1 plays a critical role in enhancing the TAM-mediated promotion of growth and metastasis in malignant melanoma and (§Discussion, final ¶) NFAT1 promotes melanoma growth and metastasis by influencing TAM properties. Grand provides evidence that (§Discussion ¶2-3; §Summary point 4) melanoma tissue, such as that used in Liu, contains melanoma cells.
Claims 1-9, 11-12, 14-19, 21, and 23-24 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUTHIE S ARIETI whose telephone number is (571)272-1293. The examiner can normally be reached M-Th 8:30AM-4PM, alternate Fridays 8:30AM-4PM (ET).
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RUTHIE S ARIETI
Examiner (Ruth.Arieti@uspto.gov)
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636