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 1-20 are pending.
Applicant’s election of the species of rubicon from claim 5 and option d (an increase in the level of M1 macrophages) (claims 17-20) in the reply filed on 10/08/2025 is re-acknowledged.
Claims 11-16 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/08/2025.
Claims 1-10 and 17-20 are under examination on the merits.
Priority
This application is a CON of US Patent Application NO. 16/606,002, filed 10/17/2019, which is a 371 of PCT/IB2018/052697, filed 04/18/2018, which claims benefit of priority to US Provisional Application No. 62/487,195, filed 04/19/2017.
Withdrawn Objections/Rejections
The objection for sequence compliance is withdrawn as corrected by the 04/30/2026 amendments to the specification (see the table in Example 1 at pages 35 bridging 36). The rejections of the claims under 35 USC §101 as presented in the previous office action are withdrawn in light of Applicant’s corrective 04/30/2026 claim amendments. In order to account for the newly added claim limitations/scope resulting from the 04/30/2026 claim amendments, the rejections of the claims under 35 USC §103 as presented in the previous office action are withdrawn and replaced with the rejections under 35 USC §103 as presented in this Office Action. It is noted that the alternative rejection of claim 8 as presented in the previous office action is withdrawn in light of Applicant’s arguments at page 15 of the 04/30/2026 remarks which articulate the incongruous teachings of Ni et al rendering the reference insufficient to support the rejection.
Maintained-Claim Interpretation
The following claim interpretations are being applied in a good faith effort to advance prosecution:
LC3-assocated phagocytosis (LAP) is understood to be and is therefore interpreted as referring to a process. Therefore, steps a and c of claim 1 which recite measuring levels of LAP in a cell population are understood to measure LAP indirectly by measuring a product/molecule that is associated with LAP. The instant specification discloses examples of molecules associated with LAP which may be used for conducting said (indirect) measurement (see page 7 bridging page 8 of the instant specification), which are being interpreted as recited by steps a and c of instant claim 1.
The recitation that the candidate molecule is selected if it reduces the level of LAP is being interpreted such that a reduction encompasses any reduction of the tested level relative to any control as is consistent with the instant specification (see pages 12 bridging 13). Likewise, because rubicon is a LAP-associated molecule, a reduction in the expression/activity of rubicon is understood to mean/encompass any reduction of the tested level relative to any control as is consistent with the instant specification (see pages 12 bridging 13).
A decrease(d) is never given a clear and closed definition in the specification. However, the specification discloses exemplary molecules which may be reduced as exemplary of a decrease in an LAP-related molecule (see page 21). Therefore, a decrease(d) is being interpreted as synonymous with a reduction such that any decrease/reduction relative to any control is encompassed by and meets the claim recitations of a decreased/decrease level (see also pages 12 bridging 13 of the instant specification).
There is no definition provided for “cancer immunity” or “promot[ing] cancer immunity”. In the interest of advancing prosecution, this recitation is being interpreted as being met by any effect which is suggested to be beneficial to treating cancer or hampering a pro-cancer immune activity (such as a decrease in LAP, and LAP-associated molecule, or a decrease in tumor-associated macrophages (TAMs) is consistent with the claim drafting, noting that “cancer immunity” is mentioned once in the specification such that the claims provide the most illustrative detail as to what Applicant intended to encompass as within the scope of the invention.
Claim 5 is being interpreted to mean that the gene activity or expression is measured indirectly by measuring the level of one of the recited options, such as the elected species of rubicon (which is a protein) associated with activity/expression of the RUBCN (KIAA0226) gene.
Regarding the limitation of “…wherein a reduction in the level of LAP comprises a decrease in LC3 lipidation…” in claims 7-8 (by recitation or dependency), the recitation is being interpreted to mean that the LC3-II (lipidated LC3 is being measured in steps a and c of the method of claim 1 as an indirect measurement of LAP), which is consistent with page 7 bridging 8 of the instant specification and with the state of the prior art as cited herein.
Regarding the limitation “…wherein…the level of LAP comprises a decrease in…,” as recited in claims 9-10, the recitation is being interpreted to mean that the limitations so modified are a result of the measured decrease in LAP (not measurements indicating decreased LAP), which is consistent with page 7 bridging 8 of the instant specification and with the state of the prior art as cited herein.
Claims 19-20 recite that the M1 macrophages produce a 50% increase in IL-1ß or a 30% increase in TNF-α relative to cells not contacted with the candidate, respectively. Given the plural recitation of macrophages, the artisan would understand the increased production is at the level of the total macrophages (not at the level of a single macrophage). Thus, a candidate expected to increase the number of M1 macrophages would be expected to result in a proportional increase in products made by M1 macrophages (for example, a candidate expected to increase the number of M1 macrophages by 50% would be expected to increase the amount of a product made by M1 macrophages (such as IL-1ß) by about 50%).
New-Claim Rejections - 35 USC § 112
35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-10 and 17-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
The examiner is unable to find support for the added limitation in claim 1 i.e., “a method of identifying a candidate non-canonical myosin associated light chain 3 (LC3)-associated phagocytosis (LAP) inhibitor… wherein the candidate LAP inhibitor from (d) is delivered to a second cell population comprising tumor cells, and wherein tumor size, number, and/or metastasis is reduced in the second cell population as compared to the tumor size, number, and/or metastasis of the second cell population not delivered the candidate LAP inhibitor”. While measurement of tumor size, number, and/or metastasis is disclosed, these measurement are disclosed are measuring a result for a method of treatment and not as being part of the process for identifying a candidate non-canonical myosin associated light chain 3 (LC3)-associated phagocytosis (LAP) inhibitor. Applicant states that support for the amendment can be found throughout the application, such as at pages 67 of the instant specification, the figures, and the Examples. However, the specification never discloses the a method of identifying a candidate non-canonical myosin associated light chain 3 (LC3)-associated phagocytosis (LAP) inhibitor wherein the candidate LAP inhibitor from (d) is delivered to a second cell population comprising tumor cells, and wherein tumor size, number, and/or metastasis is reduced in the second cell population as compared to the tumor size, number, and/or metastasis of the second cell population not delivered the candidate LAP inhibitor. This combination into a single method is not supported at any point of the specification as filed. Applicant is required to cancel the new matter in response to this office action.
Should applicant disagree with the examiner’s factual determination above, applicant should provide evidence that either or both of the provisional applications provide support for the invention now claimed in the manner required by 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. This could be accomplished, for example, by pointing to the specific page and line numbers within the specification, which disclose each limitation of the claimed invention.
35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-10 and 17-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, there is no connector between the steps (a)-(d) of claim 1. While the Examiner presumes that the method claimed requires all of steps (a)-(d), the removal of the connecting term ‘and’ resulting from the 04/30/2026 claim amendments makes the scope of the claim unclear as to whether, for example, only one of the steps or if all of the steps are required to infringe the claim as presently drafted. Additionally the recitation of ‘numbers’ in the wherein clause following step (d) of claim 1 is unclear. This recitation could refer to a number of tumor cells generally, a number of viable/live tumor cells, a number of tumors, etc. Artisans are left to dispute which interpretation of ‘numbers’ is encompassed and would infringe the claim as presently drafted.
Dependent claims 2-10 and 17-20 incorporate and fail to remedy the above noted ambiguities and are therefore included in this rejection.
New-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) 1-2, 4, and 7-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19023-8. doi: 10.1073/pnas.0709695104) in view of Kim et al (Semin Cancer Biol. 2013 Oct;23(5):329-36. doi: 10.1016/j.semcancer.2013.05.004. Epub 2013 May 30) and Kumar et al (Indian J Pharmacol. 2016 Sep-Oct;48(5):481-486. doi: 10.4103/0253-7613.190716.).
Regarding claim 1, LAP, as recited in the claims is understood to refer to LC3-associated phagocytosis, which is a process, indicating that the process is indirectly measured by measurement of some associated product/molecule (such as LC3).
The instant claim 1 comprises measuring a first level of a molecule (such as LC3) serving as an indirect measurement of LAP, contacting a first cell population with a candidate, then measuring a second level of a molecule (such as LC3) serving as an indirect measurement of LAP, contacting the candidate with a second population, LAP inhibitor that reduces the level of LAP activity following contact with the first cell population; wherein the candidate LAP inhibitor from (d) is delivered to a second cell population comprising tumor cells, and wherein tumor size, number, and/or metastasis is reduced in the second cell population as compared to the tumor size, number, and/or metastasis of the second cell population not delivered the candidate LAP inhibitor from (d).
Zhang et al sought to identify regulators of autophagy through an image-based high-throughput screen. Zhang et al teach that mammalian LC3, the ortholog of yeast ATG8, has been shown to mark the autophagosome membrane specifically. The number of LC3-GFP-positive autophagosomes per cell is very low under normal growth conditions but is rapidly increased upon serum starvation or the addition of rapamycin (positive control). Zhang et al established a human glioblastoma H4 cell line stably expressing human microtubule-associated protein (MAP) LC3-GFP. LC3-GFP specifically marks the autophagosomal membrane, and thus, each LC3-GFP spot measured/observed represents an individual autophagosome. H4-LC3-GFP cells were cultured in 96-well plates and incubated individually with 480 compounds in a known bioactive compound library (BIOMOL catalog 2840) at concentrations of 3–12µM, with the exception of rapamycin (0.22µM) and bafilomycin A1 (0.40µM)for 24 hr. The levels of autophagy were analyzed with LC3-GFP as a marker by measuring the number, size, and intensity of LC3-GFP spots with high-throughput fluorescent microscopy. DMSO and rapamycin were used as negative and positive controls, respectively (see for example, column 2 of page 9023). This screen also identified inhibitors of lysosomal function, such as bafilomycin A1, a vacuolar ATPase inhibitor, which is known to increase the numbers of intracellular autophagosomes by blocking the ability of the lysosome to degrade autophagosome (see for example, column 1 of page 19024). Note that the lipidated form of LC3 (LC3II) was also measured by western blot in the screen (see for example, column 2 of page 19025 and Fig 2 and its caption at page 19026). Thus, Zhang et al, while focusing on using the screen/assay for identification of candidate molecules that increase LAP/LC3(II), teach an assay capable of detecting candidates which decrease/reduce LC3(II) as an indicator of decreased LAP. This is deemed to read upon steps a-c of claim 1. Where comparison of the level of LAP in the first population of cells after contact with a candidate inhibitor of LAP to the level of LAP prior to contact with the LAP inhibitor would have been an obvious means of ascertaining the effect on LAP/LAP activity caused by contact with the candidate inhibitor.
Zhang et al do not teach a connection between cancer and LAP or a motivation to decrease LAP.
However, Kim et al investigated LC3-Associated Phagocytosis (LAP) in tumorigenesis (see for example, the abstract at page 1). Kim et al teach that LAP influences tumor progression and that LAP inhibition is believed to affect therapeutic responses in the setting of cancer where such therapeutic efforts are ripe for investigation (see for example, pages 8-9). Kim et al further teach that the continual rate of apoptosis that accompanies tumor progression contributes to maintaining tumor-associated macrophages (TAMs) in an M2 state, as a direct result of anti-inflammatory molecules released from apoptotic cells, or as a consequence of phagocytic clearance, as macrophages ingesting apoptotic cells are known to secrete immunosuppressive cytokines that promote M2 polarization (see for example, page 4). Kim et al additionally teach that LC3 lipidation may also facilitate antigen presentation (see for example, page 15 at the figure caption). Kim et al go on to teach that tumor associated macrophages (TAMs) and other immune cells are an important fraction of the tumor microenvironment (TME) of solid tumors, with T cells representing the major immune type (see for example, page 4).
Zhang et al and Kim et al do not explicitly teach contacting a second population (comprising tumor cells) with the candidate molecule from steps a-c and measuring a reduction in tumor size, number, and/or metastasis as indicating that the candidate is an LAP-inhibitor.
However, Kumar et al teach that in vivo evaluation of anticancer drugs usually preceded by either cellular or target-based high-throughput assays (see for example, column 2 at paragraph 1 of page 482). Cellular screens in cancer research mainly consist of permanent human tumor cell lines; most suitable test system, in terms of management, because of their immortal nature and reproducible growth behavior. A panel of sixty different human tumor cell lines from nine different types of cancer (leukemia, non-small cell lung cancer, colon cancer, brain cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer) constitute the NCI in vitro primary screen, against which compounds are tested over a defined range of concentrations to determine the relative growth inhibition or cytotoxicity against each of the cell line (see for example, column 2 of page 482 of Kumar et al). Kumar et al additionally teach that, as cancer was primarily considered a disease of uncontrolled cell division, measuring the regression in tumor size and/or identification of a cytotoxic or an antiproliferative compound was considered as the main objective endpoint of efficacy of a compound in preclinical and clinical anticancer drug development for decades (see for example, column 1 of page 482).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Zhang et al and Kim et al. The artisan would have been motivated to make and use the invention as claimed because Kim et al teach inhibition of LAP may provide benefits in the context of cancer and suggest investigation of such therapy as a next step for research which would require candidate screening prior to further, more translational investigation to elucidate LAP-inhibitory, therapeutic drug candidates. The artisan, looking to identify candidates which decrease LAP would have found it obvious to use the assay of Zhang et al as modified in light of Kim et al to comprise the cell population (comprising TAMs, T cells and tumor cells from a tumor to understand the effect(s) of the candidate in the TME) and LC3/LC3II measurement steps of Zhang et al to screen for candidates which decrease LC3/LC3II which is taught to be involved in and commonly measured as an indirect measurement for LAP (see the cited teachings from Zhang et al and Kim et al). While Zhang et al use rapamycin and DMSO as the respective positive and negative controls for comparison, the artisan would have found it obvious to use a measurement of an indicator of LAP, such as LC3/LC3II, in the cell population prior to candidate-exposure as a baseline to determine the effect of the candidate molecule on the indicator of LAP measured (as in indirect measure of LAP), such as LC3/LC3II levels, in the cells of interest. Where the goal motivated by Kim et al is to decrease LAP as measured by decreasing LC3/LC3II, the artisan would have found it obvious to select candidates which reduce the level of LC3/LC3II relative to the pre-exposure/baseline LC3/LC3II levels in order to identify candidate molecules which, by decreasing LAP would promote cancer immunity/therapeutic effects. Regarding the implied limitation of comparing said first level of LAP activity with the second level of LAP activity and the limitation of “selecting a candidate molecule that reduces the level of LAP,” the steps of comparing and selecting are mental processes that do not require any additional structure or result in a manipulative difference between the claimed method and the prior art method, and thus, the limitations do not distinguish the claimed method over the prior art method. Regarding the limitations directed toward effects of the candidate in dependent claims, it should be noted that the ability of the selected molecule to modulate/bring about the recited results, is an inherent property of the selected molecule. Regarding the claimed cell population including myeloid cells and T cells. The artisan, looking to understand the effect of decreasing LAP in TME would have found it obvious to assess the effects of the candidate and the effects on and of LAP in a sample including cell types known to be important in the TME, such as macrophages (myeloid cells) and T cells (see for example, the cited teachings of Kim et al). Moreover, where Kim et al teach that an LAP-inhibitor is helpful in treating cancer, the artisan would have been motivated to use means known in the art to evaluate the LAP-inhibitors from instant steps 1-c to select for inhibitors that are useful in treating cancer (promoting cancer immunity). Kumar et al teach that it is well established in the art to screen for anti-cancer compounds by contacting said compounds with one or more tumor cell lines and measuring the effect (looking for a reduction in) tumor size, growth, and/or metastasis (reading on step d of claim 1 as currently amended). The artisan would have had a motivated, reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Regarding claim 2, as discussed above, Kim et al teach that LAP reduction is believed to be beneficial in the setting of cancer which would motivate the artisan to take the sample from/include tumor cells.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Kim et al teach such investigation will be helpful in identifying new specific targets for cancer therapy and understanding the role of LAP inhibition in cancer therapy. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 4, as discussed above, Zhang et al teach measurement of LAP through measurement of LC3/LC3-II by western blot, immunofluorescence, flow cytometry, and microscopy (see for example, the title and pages 6-12).
The artisan would have found it obvious to use one or more of these art-known means for determining LAP.
Regarding claim 7, as discussed above, Zhang et al teach that changes in LC3II are used to measure changes in LAP (such that an increase in LC3II is an indirect measurement of an increase in LAP and a decrease in LC3II is an indirect measurement of an decrease in LAP) (see for example, column 2 of page 19025, figure 2 and its caption and column 1 of page 19026)
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed for the reasons iterated in the rejection of claim 1, where measurement of lipidated LC3 (LC3-II) as taught by Zhang et al would have been an obvious indicator/indirect measurement for LAP. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 8, it is noted that the recitation requires that the measured level of LC3II of step c is 50% reduced compared to the level of LC3-II measured in step a. Therefore, the reduction is not an active step, but is merely a result of practicing the method made obvious by the prior art.
Therefore, the prior art, upon testing of certain compounds, makes obvious this result by teaching the active steps and products required.
Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al, Kim et al, and Kumar et al, as applied to claims 1-2, 4, and 7-8 above, in further view of Tang et al (Front Oncol. 2016 Nov 9;6:236. doi: 10.3389/fonc.2016.00236).
Regarding claim 3, as discussed above, Zhang et al, Kim et al, and Kumar et al teach and make obvious the method of instant claims 1 and 2.
The combined references do not explicitly connect LAP to melanoma.
However, Tang et al teach that autophagy is a hot topic in cancer medicine, and observations of its deregulation in melanoma have brought its potential as a prognostic biomarker to the forefront of current research. Key regulatory proteins, including Atg8/microtubule-associated light chain 3 (LC3) and BECN1 (Beclin 1), have been proposed as potential prognostic biomarkers suggesting their importance in the progression of melanoma.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Zhang et al, Kim et al, Kumar et al, and Tang et al. The artisan would have been motivated to make and use the invention as claimed because Kim et al teach and suggest that such investigation will be helpful in identifying new specific targets for cancer therapy and the artisan would have understood that inclusion of tumor cells (such as a tumor explant) would be the best way to experimentally emulate the tumor microenvironment (TME) to discover/investigate how candidates may influence cancer immunity (changes in LAP in a way that better accounts for the other cellular changes acting in concert with LAP (see for example, page 9) in the MTE to effect therapeutic effects for tumors/cancers. Tang et al teach that LAP (LC3) is of particular importance in melanoma, which would guide the artisan to use tumor cells from a melanoma sample or line to investigate candidates which may be helpful in promoting cancer immunity to aid in treating/bring about one or more therapeutic effects in melanoma. The artisan would have had a motivated, reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Claim(s) 5-6 and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al, Kim et al, and Kumar et al, as applied to claims 1-2, 4, and 7-8 above, in further view of Sprenkeler et al (Cellular Microbiology (2016) 18(9), 1208–1216; doi:10.1111/cmi.12616; First published online 6 July 2016) and Matsunaga et al (Nat Cell Biol 11, 385–396 (2009); https://doi.org/10.1038/ncb1846).
Regarding claims 5-6, as discussed above, Zhang et al, Kim et al, and Kumar et al teach and make obvious the method of instant claim 1, but do not explicitly discuss the role of rubicon in LAP.
However, Sprenkeler et al teach that LC3-associated phagocytosis (LAP) is a non-canonical autophagy pathway involved in the maturation of single-membrane phagosomes and subsequent killing of ingested pathogens by phagocytes (see for example, the summary paragraph at page 1208). Sprenkeler et al further teach that the autophagy protein rubicon was recently identified to be required for the induction of LAP, while it is a non-essential protein for the induction of autophagy (citing to Martinez et al., 2015). Sprenkeler et al additionally teach that rubicon has been previously described as a negative regulator of autophagy, especially in the maturation of the autophagosome (citing to Matsunaga et al., 2009). Sprenkeler et al go on to teach that rubicon-deficient macrophages fail to recruit LC3 to phagosomes, while conventional phago-cytosis and autophagy were still occurring (see for example, column 1 of page 1211).
While Sprenkeler et al teach motivation to measure rubicon as an indirect measure of LAP, Sprenkeler et al do not explicitly teach said measurement.
However, Sprenkeler et al cite to Matsunaga et al who teach ways known in the art for measuring rubicon (see for example, pages 386-388 and 391-393).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Zhang et al, Kim et al, Kumar et al, Sprenkeler et al, and Matsunaga et al. The artisan would have been motivated to make and use the invention as claimed because Kim et al teach that autophagy, and autophagy driven by LC3-II (LAP), is believed to play a role in cancer and that inhibition of LAP is believed to be therapeutic in the setting of cancer. The artisan, looking to treat cancer would have understood the desirability of decreasing LAP in the setting of cancer. One way of doing this would be to reduce the levels/expression/activity of molecules required for LAP, such as rubicon. The artisan, looking to identify candidates which decrease LAP would have found it obvious to use the assay of steps of Zhang et al modified to comprise the cell population and LC3/LC3II measurement steps of Zhang et al and Matsunaga et al and to screen for candidates which decrease LC3/LC3II and rubicon which are taught to be required for LAP (see the cited teachings above). While Zhang et al use rapamycin and DMSO as the respective positive and negative controls for comparison, the artisan would have found it obvious to use a measurement of LC3/LC3II and rubicon in the cell population prior to candidate-exposure as a baseline to determine the effect of the candidate molecule on the LC3/LC3II and rubicon levels in the cells of interest. Where the goal is to decrease LAP as measured by decreasing LC3/LC3II, the artisan would have found it obvious to select candidates which reduce the level of LC3/LC3II and rubicon relative to the pre-exposure/baseline LC3/LC3II levels in order to identify candidate molecules which, by decreasing LAP would promote cancer immunity/be beneficial in the setting of cancer. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 9, Sprenkeler et al teach that rubicon associates with the UVRAG (UV radiation resistance-associated gene)-containing class III PI3K complex, resulting in generation of phosphatidylinositol 3-phosphate (PI(3)P) on the phagosomes. PI(3)P is required for the progression of LAP, and it stabilizes the NADPH oxidase complex by binding to p40phox (citing Ueyama et al., 2011; additionally citing Martinez et al., 2015). Rubicon is also thought to stabilize the NADPH oxidase complex directly, resulting in optimal ROS production (citing Boyle and Randow, 2015; additionally citing Martinez et al., 2015).
Note that it is unclear whether or not the recited reduction in ROS is what is being measured in steps a and c of claim 1 or if the reduction in ROS is a result comprised by a reduction in LAP (stemming from reducing LAP). The Examiner is interpreting the recited reduction to be a result stemming from reducing LAP in light of the passive claim drafting.
The limitations of claim 9 are obvious for the same reasons for which claim 1 is obvious.
Claim(s) 9-10 and 17-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al, Kim et al, and Kumar et al, as applied to claims 1-2 and 4-10 above, in further view of Martinez et al-2013 (J Mol Biol. 2017 November 24; 429(23): 3561–3576. doi:10.1016/j.jmb.2017.08.012).
Regarding claim 9, as discussed above, Zhang et al, Kim et al, and Kumar et al teach the method of claim 1 and are held to make obvious the effect of a decrease in ROS resulting from decreased LAP.
However, if the decreased ROS is intended to reflect the indirect measurement recited in steps a and c of claim 1, the combination of references do not clearly explain why this finding would have been an obvious indictor of a decrease in LAP.
However, Martinez et al-2013 teach that it has been reported that ROS (a hallmark for M1 macrophages), specifically via the NADPH oxidase 2 (NOX2), is required for LC3 translocation to the particle-containing phagosome and NOX2-deficient macrophages fail to engage the autophagic machinery (citing to Huang et al., 2009) (see for example, column 2 of page 899).
Because Martinez et al-2013 teach that NOX2 is needed for ROS production, which is needed for LAP, the artisan would have also found it prima facie obvious to measure the amount of a molecule necessary for LAP, understanding that a decrease in a necessary molecule would decrease the activity/process for which it is needed.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Zhang et al, Kim et al, Kumar et al, and Martinez et al. The artisan would have been motivated to make and use the invention as claimed because Martinez et al-2013 teach that NOX2 is needed for ROS production, which is needed for LAP, Zhang et al teach an assay and Zhang et al as modified by Kim et al and Kumar et al teach an assay for screening a compound that reduces LAP for a therapeutic effect in tumors/cancer. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Regarding claim 10, as discussed above, Zhang et al, Kim et al, and Kumar et al teach the method of claim 1.
The combined references do not clearly teach why the artisan would expect an decrease in NOX2 to cause or result from a decrease in LAP.
However, Martinez et al-2013 teach that it has been reported that ROS (a hallmark for M1 macrophages), specifically via the NADPH oxidase 2 (NOX2), is required for LC3 translocation to the particle-containing phagosome and NOX2-deficient macrophages fail to engage the autophagic machinery (citing to Huang et al., 2009).
Note that it is unclear whether or not the recited reduction in NOX2 what is being measured in steps a and c of claim 1 or if the reduction in NOX2 is a resulted comprised by a reduction in LAP (stemming from reducing LAP). The Examiner is interpreting the recited reduction to be a result of reducing LAP in light of the passive claim drafting. However, because Martinez et al-2013 teach that NOX2 is needed for ROS production, which is needed for LAP, the artisan would have also found it prima facie obvious to measure the amount of a molecule necessary for LAP, understanding that a decrease in a necessary molecule would decrease the activity/process for which it is needed.
The limitations of instant claim 10 are obvious for the same reasons which instant claim 1 is obvious.
Regarding claim 17, as discussed above, Zhang et al, Kim et al, and Kumar et al teach the method of claim 1.
The combined references do not clearly teach why the artisan would expect an increase in M1 macrophages as a result of administering a candidate molecule which reduces LAP.
However, Martinez et al-2013 teach that LAP exerts impacts upon the immune response as well (see for example, page 898). Because successful LAP during the engulfment and degradation of dead cells results in an anti-inflammatory cytokine response, the involvement of PPARγ and acquisition of an M2 phenotype is anticipated (see for example, page 899 of Martinez et al-2013). Martinez et al-2013 review observations that suggest that LAP is be required to maintain an anti-inflammatory (characteristic of M2 macrophages versus M1 macrophages) environment. Martinez et al-2013 further explain that signal specificity during LAP plays a part in dictating both the immune response as well as the metabolic response (see for example, page 899). Martinez et al-2013 additionally teach that M1 macrophages produce nitric oxide (NO), reactive oxygen species (ROS), and proinflammatory cytokines, such as TNF-α, interleukin-1ß (IL-1ß), IL-6, and IL-12, thus mounting a rapid, effective response against highly proliferative intracellular pathogens (see for example, page 895 at column 1 bridging column 2 and page 899).
It is noted that the increase by any amount, including 50%, is a result of contacting the candidate with the cell population, said result being an obvious indirect measurement of LAP because LAP influences macrophage polarization to a M2 state, where measurement of M1 (increase) or M2 (decrease) allows for inferences to be drawn regarding changes in LAP because it is an effect of modulating LAP taught in the prior art. Note that the present drafting does not require measurement of M1 macrophages or any active step related thereto.
Moreover, The MPEP provides that:
"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel." Id. See also MPEP 2112(I) with regard to inherency and product-by-process claims and MPEP § 2141.02 with regard to inherency and rejections under 35 U.S.C. 103,”
(see MPEP 2112(I)).
The limitations of instant claim 17 are obvious for the same reasons which instant claim 1 is obvious. Therefore, the cited references and teachings are held to make obvious as of the filing date the method of claim 1 where a screened candidate molecule increases the measured number of M1 macrophages by 50% relative to a pre-exposure/baseline measurement of M1 macrophages, absent evidence to the contrary.
Regarding claim 18, as discussed above, the reduction, including a reduction by 50% as recited in claim 18, is not an active step, but merely recites a result of practicing the method of claim 1, which is therefore obvious for the same reasons that the method of claims 1 and 17 are obvious.
Regarding claim 19, as discussed above, Zhang et al, Kim et al, and Kumar et al teach the method of claim 1. Zhang et al, Kim et al, Kumar et al, and Martinez et al-2013 teach and make obvious the method of instant claims 17-18. Martinez et al-2013 further teach that M1 macrophages produce proinflammatory cytokines, such as TNF-α and interleukin-1ß (IL-1ß) (see for example, column 1 bridging column 2 of page 895). Where the combined references teach that a candidate that decreases LAP would be expected to result in an increased number of M1 macrophages (by altering their polarization towards an M1 state). Where the number of M1 cells in the sample is made obvious to increase, it is further obvious to expect a corresponding/proportional increase in production of products made by M1 macrophages, absent evidence to the contrary.
Moreover, The MPEP provides that:
"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel." Id. See also MPEP 2112(I) with regard to inherency and product-by-process claims and MPEP § 2141.02 with regard to inherency and rejections under 35 U.S.C. 103,”
(see MPEP 2112(I)).
The increase in IL-1ß, including a 50% increase, by M1 macrophage after exposure to the candidate molecule is not an active step, but merely recites a result of practicing the method of claim 1, which is therefore obvious for the same reasons that the method of claims 1 and 17 are obvious.
Regarding claim 20, as discussed above, Zhang et al, Kim et al, and Kumar et al teach the method of claim 1. Zhang et al, Kim et al, Kumar et al, and Martinez et al-2013 teach and make obvious the method of instant claims 17-18. Martinez et al-2013 further teach that M1 macrophages produce proinflammatory cytokines, such as TNF-α and interleukin-1ß (IL-1ß) (see for example, column 1 bridging column 2 of page 895). Where the combined references teach that a candidate that decreases LAP would be expected to result in an increased number of M1 macrophages (by altering their polarization towards an M1 state). Where the number of M1 cells in the sample is made obvious to increase, it is further obvious to expect a corresponding/proportional increase in production of products made by M1 macrophages, absent evidence to the contrary.
Moreover, The MPEP provides that:
"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel." Id. See also MPEP 2112(I) with regard to inherency and product-by-process claims and MPEP § 2141.02 with regard to inherency and rejections under 35 U.S.C. 103,”
(see MPEP 2112(I)).
The increase in TNF-α, including an increase of 30%, by M1 macrophage after exposure to the candidate molecule is not an active step, but merely recites a result of practicing the method of claim 1, which is therefore obvious for the same reasons that the method of claims 1 and 17 are obvious.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al, Kim et al, and Kumar et al, as applied to claims 1-2 and 4-10 above, in further view of Martinez et al-2013 (J Mol Biol. 2017 November 24; 429(23): 3561–3576. doi:10.1016/j.jmb.2017.08.012) and Schiavone et al (Transl Psychiatry. 2016 May 17;6(5):e813. doi: 10.1038/tp.2016.76).
Regarding claim 10, as discussed above, Zhang et al, Kim et al, and Kumar et al teach the method of claim 1 and are held to make obvious the effect of a decrease in ROS produced by NOX2 resulting from decreased LAP.
However, if the decreased NOX2 is intended to reflect the indirect measurement recited in steps a and c of claim 1, the combination of references do not clearly explain why this finding would have been an obvious indictor of a decrease in LAP.
However, Martinez et al-2013 teach that it has been reported that ROS (a hallmark for M1 macrophages), specifically via the NADPH oxidase 2 (NOX2), is required for LC3 translocation to the particle-containing phagosome and NOX2-deficient macrophages fail to engage the autophagic machinery (citing to Huang et al., 2009) (see for example, column 2 of page 899).
Because Martinez et al-2013 teach that NOX2 is needed for ROS production, which is needed for LAP, the artisan would have also found it prima facie obvious to measure the amount of a molecule necessary for LAP, understanding that a decrease in a necessary molecule would decrease the activity/process for which it is needed.
The cited references motivate measurement of NOPX2, but do not explicitly teach ways to measure NOX2.
However, Shiavone et al teach measurement of NOX2 (see for example, column 2 of age 2).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Zhang et al, Kim et al, Kumar et al, Martinez et al, and Shiavone et al. The artisan would have been motivated to make and use the invention as claimed because Martinez et al-2013 teach that NOX2 is needed for ROS production, which is needed for LAP, Zhang et al teach an assay and Zhang et al as modified by Kim et al and Kumar et al teach an assay for screening a compound that reduces LAP for a therapeutic effect in tumors/cancer. The artisan would have had a motivated, reasonable expectation of success prior to the effective filing date based on the cumulative disclosures of these prior art references.
Applicant’s Arguments and Responses
A. Applicant argues for withdrawal of the rejections of the claims under 35 USC §103 by arguing a lack of motivation to combine Zhang et al and Kim et al as well as arguing the artisan would have thought that Zhang et al was concerned with canonical not non-canonical autophagy (see for example, pages 11-12 of the 04/30/2026 remarks).
Response: The motivation to combine Zhang et al and Kim et al is articulated clearly in the rejections under 35 USC §103 as presented in this Office Action above. The argument that there is no prima facie case because there is no articulated motive to combine is therefore unpersuasive. Second, Applicant cherry picks from Zhang et al and attempts to alter the instant claim preamble to overcome the clearly relevant teachings of Zhang et al. This is unpersuasive because where Zhang et al in view of Kim et al and Kumar et al teach, motivate, and make obvious a method of screening for a candidate LAP inhibitor having the same steps as the instantly claimed method with the same selection criteria, the method would result in selection of the same non-canonical LAP inhibitors absent a clear and evidenced showing to contrary. As discussed in the rejection above, while the focus of Zhang et al teaches a screen for candidates that increase LAP (as indirectly measured through LC3II), Zhang teaches measurement of LAP activity as a screen where the artisan, motivated to screen for LAP-inhibitors by the teachings of Kim et al would understand that measurement of LAP activity as taught by Zhang et al with selection for inhibitors that decrease LAP activity would have been well within the understanding and ability of one of ordinary skill in the art. Note that, the MPEP provides that,
“A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.”KSR, 550 U.S. at 421, 82 USPQ2d at 1397. “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.”Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.”Id. at 418, 82 USPQ2d at 1396,”
(see MPEP § 2141 (II)(c)). Therefore, these arguments are not persuasive and the rejections under 35 USC §103 as presented in this Office Action are maintained.
B. Applicant argues for withdrawal of the rejections of the claims under 35 USC §103 by arguing that Kim et al teach away from using a non-canonical LAP-inhibitor for cancer (see for example, page 13-15).
Response: Kim et al, while teaching that LAP-inhibitors may be helpful in treating cancer, but that there may be a degree of unpredictability does not teach away from using LAP-inhibitors to treat cancer and especially does not teach away from screening for LAP-inhibitors and testing them for their anti-cancer effect in vitro. Kim et al acknowledge that the TME is a complex environment, but that does not discourage or discredit screening for LAP-inhibitors that decrease tumor size, number, and/or metastasis, particularly where such screening for compounds that decrease tumor size, number, and/or metastasis is well-known in the art (as taught by Kumar et al as discussed in the rejections under 35 USC §103 above) and acknowledged to be a first step in finding therapeutic cancer candidates. Additionally, what is claimed is a screening method, not a method of treating cancer. Here, the artisan must merely be motivated by the prior art to screen for an LAP-inhibitor, screening is a common first step in identifying cancer treatments where the concerns of unpredictability are significantly less likely to dissuade the artisan. Additionally, Applicant argues that the compound identified by the prior art method may also identify compounds that inhibit both canonical and non-canonical LAP. The claim as drafted does not preclude this. Further, where the steps and reagents of the instantly claimed method and the method made obvious by the prior art are the same, they are presumed logically to identify the same candidate agents. This argument is unpersuasive and the rejections as presented in this Office Action are maintained.
C. Applicant argues for withdrawal of the rejections of the claims under 35 USC §103 (see for example, pages 15-17).
Response: Regarding the arguments related to Tang et al, Sprenkeler et al, and Matsunaga et al Applicant only discusses the references in isolation. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant argues that there is no reasonable expectation of success that LAP inhibitors would impede tumor progression. This is not a requirement of the claims as drafted. The claims merely pertain to screening for a candidate LAP-inhibitor that promotes cancer immunity by resulting in a measured decrease in tumor size, number, and/or metastasis when contacted with a cell population comprising tumor cells, which the combined references motivate with a reasonable expectation of success (where the end point is the method for screening not a method of treating cancer) for reasons iterated in the rejections under 35 USC §103 above. What is claimed is a method of screening. There are no reasons articulated and evidenced in Applicant’s 04/30/2026 remarks to support that the method of screening made obvious by the prior art would fail to screen for LAP-inhibitors which may be selected where they reduce tumor size, number, and/or metastasis as instantly claimed. The rejections as presented in this Office Action are therefore maintained at this time.
D. Applicant argues that the rejections of the claims under 35 USC §103 as presented in the previous office action did not account for the newly added limitations resulting from the 04/30/2026 claim amendments.
Response: The Examiner has withdrawn the rejections of the claims under 35 USC §103 as presented in the previous office and replaced them with the rejections under 35 USC §103 as presented in this Office Action which are deemed to account for the newly added limitations resulting from the 04/30/2026 claim amendments.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights