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 acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 11-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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.
IDS
The information disclosure statement (IDS) filed 08/15/2022 has been considered.
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%).
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
35 U.S.C. 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-10 and 17-20 are rejected under 35 U.S.C. 101, because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim is directed to a judicial exception (a natural correlation), specifically, a method of identifying a candidate molecule that promotes cancer immunity. Furthermore the claim does not integrate said judicial exception in to practical application, and the claim does not recite additional elements that amount to significantly more than said judicial exception.
Where a claim describes a judicial exception, such a claim “requires closer scrutiny for eligibility because of the risk that it will ‘tie-up’ the excepted subject matter and pre-empt others from using [the judicial exception]" (federal register, p.74622, C1). While all inventions to some degree involve natural laws, products, and other judicial exceptions, the new guidance regarding patent eligibility makes clear that a practical application of these exceptions is necessary, offering “significantly more” than the exception itself. Limitations that were found not to be enough to qualify as “significantly more” include:
Mere instructions to implement an abstract idea on a computer;
Adding generic instructions that the judicial exception should be used ("apply it");
Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality;
Adding insignificant extra solution activity to the exception ("mere data gathering"); and
Generally linking the use of the exception to a particular technological environment or field of use.
The MPEP (see § 2103-2106.07) provides a means of determining whether a particular claim is patent eligible under 35 U.S.C. 101. The Guidance requires an analysis of multiple steps, Steps 1, 2A, and 2B:
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A.
Step 2A - A two-prong analysis. For prong one, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong two, which asks whether the claim recites additional elements that integrate the judicial exception into a practical application. If “No,” the analysis moves on to step 2B.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
In the instant case, the claims are drawn to a process, so the answer to Step 1 is “Yes.”
With respect to prong one of Step 2A, the answer is “Yes,” because as indicated above, the claims are drawn to mathematical concepts.
Claim 1 is directed to a method of identifying a candidate molecule that promotes cancer immunity, the method comprising: (a) measuring a first level of non-canonical myosin associated light chain 3 (LC3)-associated phagocytosis (LAP) in a cell population comprising myeloid cells and T cells; (b) contacting the cell population with at least one candidate molecule; (c) measuring a second level of LAP in the cell population; and (d) selecting a candidate molecule that reduces the level of LAP following contact with the cell population. Claims 2-4 and 17 only further limit the cell population used in the method of claim 1 or the measurement steps. Claims 5-6 only further add the step of measuring the expression or activity of a gene. Claims 7-10 and 18-20 only recite effects noted from practicing the method of claim 1. Thus, claims 2-10 and 17-20 incorporate and fail to remedy the deficiency of claim 1, from which they depend.
Regarding claim 1, the claim language reciting the judicial exception is found in the claim preamble and in step d.
Step 1 - Following a determination of the broadest reasonable interpretation of a claim, is the claim drawn to a process, machine, manufacture, or composition of matter? If the answer to this inquiry is “Yes,” the analysis moves on to step 2A. Here, the instant claim 1 recites, “A method for identifying….” Therefore, the instant claim 1 is directed towards a method, which is a process under 35 U.S.C. 101. So the answer to step 1 is “YES.” Thus, the analysis proceeds to Step 2A.
Step 2A - A two-prong analysis. For prong 1, does the claim recite an abstract idea, law of nature, or natural phenomenon? If “Yes,” the analysis proceeds to prong 2, which asks whether the claim integrates the judicial exception into a practical application. If “No,” the analysis moves on to step 2B. Here, the instant claim 1 includes step d directed to a mental step of selecting cells, which is a judicial exception. Therefore, the answer to prong 1 of step 2A is “YES.” Thus, the analysis proceeds to prong 2 of step 2A. Here, the instant claim 1 fails to recite any claim limitations which would integrate the recited judicial exception, for example, by applying or using said judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? If “No,” the claim is not eligible subject matter under 35 U.S.C. 101.
The additional claim elements are insufficient to amount to significantly more than the judicial exception for the following reasons.
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
The additional steps a and c (measurement steps) are deemed to reflect mere extrasolution activity and do not add significantly more. Step b of contacting the cell population with at least one candidate molecule does not add a meaningful limitation to the instant method as this step is mere extrasolution activity implied and required for steps c-d.
For all of these reasons, the steps of contacting cells with a candidate molecule and taking measurements do not add ‘significantly more,’ (see Mayo v. Prometheus, 566 U.S.66, 132 SA. Ct. 1289). The claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s) recited in step 1c.
Therefore, the answer to prong 2B is “No” and the instant claim 1 is therefore directed toward patent ineligible subject matter under 35 U.S.C. 101 and is therefore rejected under 35 U.S.C. 101.
Dependent claims 2-10 and 17-20 incorporate the judicial exception of claim 1 and further fail to set forth limitations which would integrate the method of claim 1 or which may make the subject matter of claim 1 patent-eligible through adding ‘significantly more’.
Therefore, claims 1-10 and 17-20 are rejected under 35 USC §101 as being directed towards patent ineligible subject matter, failing to integrate or add significantly more so as to transform the metes and bounds of the claims into subject matter eligible for patentability.
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. )
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 cell population with a candidate, then measuring a second level of a molecule (such as LC3) serving as an indirect measurement of LAP, with the goal of selecting a candidate that reduces LAP as measured by a reduction in the second level relative to the first level.
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.
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).
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). The artisan would have had a reasonable expectation of success 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 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 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 Zhang et al and Kim et al. 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, and Kim 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 and Kim 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, 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 reasonable expectation of success 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 and Kim 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 and Kim 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, 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) 8 is/are alternatively rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al and Kim et al, as applied to claims 1-2, 4, and 7-8 above, in further view of Ni al (Autophagy 7:2, 188-204; February 2011).
Regarding claim 8, while Zhang et al and Kim et al are deemed to make obvious the limitations of instant claim 8, Ni et al augment this teaching by showing that a low concentration of CQ (10 μM) reduced lipidated LC3 by 50% which points to 50% reduction as a measurement indicating a reduction in LAP, but not a total cessation/inhibition of LAP.
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, and Ni 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 involved in cancer and that inhibition or reduction of LAP is believed to be beneficial in cancer treatment as LAP is believed to be involved in tumorigenesis (see for example, page 9). The artisan, looking to treat cancer would have understood the desirability of decreasing LAP for cancer therapy/promotion of cancer immunity. The artisan, looking to identify candidates which decrease LAP would have found it obvious to use the assay of steps of Zhang et al as modified to screen for candidates which decrease LC3/LC3II. The artisan, in light of the cited teachings of Ni et al, would have found it obvious to select for candidates which decrease LC3/LC3-II by 50% relative to the baseline/pre-exposure level. 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 in the cell population prior to candidate-exposure as a baseline to determine the effect of the candidate molecule on the LC3/LC3II 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 relative to the preexposure/baseline LC3/LC3II levels in order to identify candidate molecules which, by decreasing LAP would promote cancer immunity. The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Claim(s) 9-10 and 17-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al and Kim 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 and Kim 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, 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 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 and Kim 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 and Kim 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 and Kim et al teach the method of claim 1. Zhang et al, Kim 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 and Kim et al teach the method of claim 1. Zhang et al, Kim 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 and Kim 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 and Kim 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, 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 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.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Green et al (Cell. 2014 Mar 27;157(1):65-75. doi: 10.1016/j.cell.2014.02.049) is deemed relevant.
Mills et al (Cancer Res. 2016 Feb 1;76(3):513-6. doi: 10.1158/0008-5472.CAN-15-1737. Epub 2016 Jan 15) is deemed relevant because Mills et al teach that modulating M2/repair-type macrophages to M1/kill-type can slow or stop cancer growth. The effects involve direct activity of M1 kill-type as well as the ability of M1-type macrophages to stimulate Th1-type cytotoxic T cells and other effector cells. Macrophage responses can also predict cancer susceptibility; individuals with a high M1/kill to M2/repair ratio are less prone.
Fernandez-Boyanapalli et al (PPARγ activation normalizes resolution of acute sterile inflammation in murine chronic granulomatous disease. Blood. 2010; 116(22):4512-4522) is deemed relevant and teach a method of identifying a molecule that modulates LAP activity by teaching measuring a first level of LAP activity (PPARγ and IL-10) in CGD-deficient macrophages.
Bae et al (Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2. Circ Res. 2009; 104:210-218) teach a method of identifying a molecule that modulates (includes increasing or decreasing) LAP activity by teaching measuring a first level of LAP activity (MCP-1, IL-10, TNFα, IL-1β, RANTES, MIP-1α, MIP-2 and IL-6) in NOX2-deficient peritoneal resident macrophages in the absence of mmLDL; contacting the NOX2-deficient peritoneal resident macrophages with mmLDL; measuring a second level of LAP activity (MCP-1, IL-10, TNFα, IL-1β, RANTES, MIP-1α, MIP-2 and IL-6) after said contacting with the mmLDL (see for example, pages 213-217 and figures 6 and 7).
Harris et al (J Biol Chem. 2011 Mar 18;286(11):9587-97. doi: 10.1074/jbc.M110.202911) is deemed relevant. Harris et al teach a method of identifying a molecule that modulates LAP activity by teaching measuring a first level of LAP activity (IL-1β) in NOX2-/- immortalized bone marrow macrophages (iBMM) in the absence of 3MA; contacting the NOX2-/- iBMMs with 3MA; measuring a second level of LAP activity (IL-1β) after said contacting with the 3MA (See pages 9592 and figure 4). Harris et al teach measuring LAP activity (IL-1β) in a control cell deficient in NOX2 (See page 9592 and figure 4). Harris et al teach that 3MA increases LAP activity (IL-1β) (See page 9592 and figure 4). Harris et al teach that iBMMs were generated from gp91phox (NOX2)-/- mice (See page 9588).
Mishran et al (Am J Respir Cell Mol Biol. 2013 Oct;49(4):503-10. doi: 10.1165/rcmb.2013-0086MA) teach measurement of M1 macrophages using flow cytometry.
Ngabire et al (Int. J. Mol. Sci. 2017, 18, 2016; doi:10.3390/ijms18092016) teach that LC3-II (also called the LC3-PE complex) is very important for the fusion of autophagosomes with lysosomes (LC3-assoicated phagocytosis (LAP)) (see for example, pages 3 bridging 4). Ngabire et al further teach that autophagy plays a major role in cancer, particularly in the tumor microenvironment where it has a paradoxical function in acting as a tumor suppressor and also as a tumor promoter. In the tumor microenvironment, autophagy regulates the differentiation of macrophages into tumor-associated macrophages (TAMs) and fibroblasts into cancer-associated fibroblasts (CAFs). TAMs and CAFs are abundantly present in the tumor microenvironment, and participate actively in tumor growth, tumor invasiveness, and tumor resistance to chemotherapy (see for example, the abstract at page 1).
Heckmann et al (J Mol Biol. 2017 November 24; 429(23): 3561–3576. doi:10.1016/j.jmb.2017.08.012) teach that the link between LC3-associated phagocytosis (LAP) and clearance of apoptotic cells by efferocytosis hints at a deeper involvement for LAP in the regulation of macrophage metabolism and polarization. Macrophage functions are defined in response to microenvironmental cues, such as recognition of dying cells, that drive the acquisition of a spectrum of polarization states that find their extremes in either a pro-inflammatory (M1) or anti-inflammatory (M2). Since efferocytosis is typically immunologically silent, an anti-inflammatory M2-like response is observed in response to apoptotic cells. However, mice that are LAP-deficient tend to have a pro-inflammatory (M1) response when challenged with dead cells (see for example, the abstract at page 1 and page 10).
Martinez et al (Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat Cell Biol 17, 893–906 (2015); https://doi.org/10.1038/ncb3192 (as cited and incorporated by reference at page 7 of the instant specification ["any method known in the art can be used for measuring LAP activity, including those described in Martinez et al. (2015) Nature Cell Biology 17: 893-906, herein incorporated by reference in the entirety"]; retracted 03/04/2024) Martinez et al characterized the molecular requirements for LC3-associated phagocytosis (LAP) and identify a protein, rubicon, required for LAP but not canonical autophagy (see for example, the abstract at page 893). Martinez et al teach SDS-PAGE analysis of centrifuged cell lysates using anti-LC3B (catalogue no. ab48394) from abCam and anti-Rubicon (clone D9F7, catalogue no. 8465) and anti-LC3A (clone D50G8, catalogue no. 4599) from Cell Signaling (see for example, pages 907-908 of the copy provided in this Office Action; see also for example, figure 1f at page 894, 2i at page 896, 3f and 3h at page 897, page 4f at page 899, 5a at page 900, 6g at page 902 and their respective captions; note that detection/analysis through flow cytometry and immunofluorescence are also taught, see for example, page 908). Martinez et al focus their analysis and discussion on a population of cells including T cells and macrophages (myeloid cells) (see for example, column 1 of page 895 and page 907). et al teach that the formation/maturation of macrophages to LAPosomes (required for LAP) requires the presence of LC3-II (lipidated LC3) (see for example, figure 8 and its caption at page 904). Martinez et al teach that LC3 (mammalian homologue of Atg8) is the most commonly monitored autophagy-related protein, and its lipidated form, LC3-II, is present on autophagosomes during canonical autophagy see for example, pages 893, Figure 1f and its caption at page 894, figure 2i and its caption at page 896, figure 3f and its caption at page 897, figure 4f and its caption at page 899, figure 5 and its caption at page 900, and figure 6 and its caption at page 902). Martinez et al teach that rubicon stabilizes the NOX2 complex for reactive oxygen species (ROS) production, both of which are critical for progression of LAP (see for example, the abstract and column 2 at page 893, and pages 899 and 907). It is noted that the reduction in NOX2 is a result of contacting the candidate with thy cells, said result being an obvious indirect measurement of LAP because NOX2 is needed for ROS production which is needed for LAP progression, where measurement of NOX2 allows for inferences to be drawn regarding changes in LAP. Note that the present drafting does not require measurement of NOX2 or any active step related thereto. Note that Martinez et al teach measurement of NOX2 (see for example, page 897).
Gottlieb et al (Circ Res. 2015 Jan 30;116(3):504-14. doi: 10.1161/CIRCRESAHA.116.303787), investigating autophagy, teach measurement of LC3II by western blot (see for example, the title and pages 6-7 and 9), immunostaining of puncta (see for example, pages 6-8), microscopy (see for example, para 1 at page 9, GFP-RFP-LC3 assays (see for example, page 10), optical imaging of fluorescent proteins (see for example, page 11), and flow cytometric measurement/analysis of LC3 (see for example, page 12). Gottlieb et al additionally teach that detection of autophagy in humans is restricted to biochemical or microscopy analysis of biopsies
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678