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 .
Election/Restrictions
Applicant’s election without traverse of the following species:
colorectal cancer and MMR-proficient as the elected species of cancer;
TMZ as the elected species of imidazotetrazine chemotherapeutic agent;
cisplatin as the elected species of platinum-containing chemotherapeutic agent species; and
nivolumab as the elected immune checkpoint inhibitor species,
in the reply filed on July 27, 2026 is acknowledged.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on June 20, 2023, wherein claims 1-13, 18, 20, 22, 24, and 38-95 are canceled; claims 14-15 are unchanged; claims 16-17, 19, 21, 23 and 25-37 are amended.
Claims 14-17, 19, 21, 23 and 25-37 are pending and under examination in accordance with the elected species.
Priority
The instant application 17/792,557 filed on June 20, 2023 is a 371 of PCT/US21/13212 filed
on January 13, 2021, which claims priority to, and the benefits of U.S. Provisional Application No.
62/960,464 filed on January 13, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/20/2023 and 3/25/2026 are in compliance with the provisions of 37 CFR 1.97 unless otherwise noted. Accordingly, the information disclosure statements are being considered by the examiner.
ClinicalTrials studies NCT02983045, NCT03832621, NCT03872947, NCT03879811 and NCT04457284 (cited under “Non-Patent Literature Documents”, no. 8 to no. 12 in IDS filed on June 20, 2023) is partially cropped, thus, unreadable. While applicant has attempted to provide a legible copy of these references in the application file, these documents cited in the IDS have not been considered by the Examiner.
Please note there are two information disclosure statements submitted on 3/25/2026, and one of them appears to be duplicated with the same reference cited. Therefore, one of them has been cross-out, but the references recited therein has already been considered by the Examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because of the following informalities:
Figure. 1A-E: the numerical numbers, texts (e.g., “
PNG
media_image1.png
75
122
media_image1.png
Greyscale
”), units (including x-axis and y-axis), bar/line graphs, and symbols illustrated therein are blurry and unreadable. It is not clear which line or bar corresponds to which group listed on the side as they appear to have similar color and pattern.
Figure. 2: the text appears to be blurry and unreadable (e.g., “
PNG
media_image2.png
74
120
media_image2.png
Greyscale
”). The graph uses same shade of gray to label more than group (e.g., “
PNG
media_image3.png
21
132
media_image3.png
Greyscale
” and “
PNG
media_image4.png
19
127
media_image4.png
Greyscale
”), and it not clear which shade of gray corresponds to which group listed on the right-hand side.
Figure. 3B: the text and number appear to be blurry and unreadable.
Figure. 3C: the text, units (including x-axis and y-axis), and labeling of each group appear to be blurry and unreadable.
Figure 4A-4B: more than one group appear to be using same shade of gray and pattern (e.g., “
PNG
media_image5.png
47
189
media_image5.png
Greyscale
”; “
PNG
media_image6.png
51
140
media_image6.png
Greyscale
”), thus, it is not clear which line or bar corresponds to which group listed on the side.
Fig. 5: the text, numbers and units (including x-axis and y-axis) appear to be blurry and unreadable. More than one group appears to be using same shade of gray (see e.g., “
PNG
media_image7.png
36
38
media_image7.png
Greyscale
”), and it is not clear which shade of gray corresponds to which group listed on the side.
Fig. 6: the text, numbers and units (including x-axis and y-axis) appear to be blurry and unreadable. The line for each group is clustered together in the line graph, making it difficult to tell which line represents which group. Some groups appear to have the same pattern and same shade of gray (e.g.,
PNG
media_image8.png
22
84
media_image8.png
Greyscale
), and it is not clear which pattern and shade corresponds to which group listed on the side.
The examples provided within the parenthesis are intended to demonstrate, at a minimum, the issues identified and should not be construed as encompassing each and every issue in its entirety. Applicant is required to carefully check the entire drawings for any, and all issues noted above.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Interpretation
The claimed term “treating”, when reasonably construed in view of the definition provides in paragraph [0076] of the specification shown below:
PNG
media_image9.png
235
716
media_image9.png
Greyscale
PNG
media_image10.png
80
729
media_image10.png
Greyscale
, is taken to include preventing.
The claimed term “about”, when reasonably construed in view of the definition provides in paragraph [0031] of the specification shown below:
PNG
media_image11.png
60
722
media_image11.png
Greyscale
, is taken encompass ± 10% of a specified amount; therefore, the phrase “about… to about…” is taken to include the range, where the lower limit is calculated as the specified amount minus 10% of that amount, and the upper limit is calculated as the specified amount plus 10% of that value. For example, if the range is “about 50-200”:
Lower limit:
50
-
0.1
×
50
=
45
g
Upper limit:
200
+
0.1
×
200
=
220
g
, said range is reasonably interpreted as 45 g to 220 g. Similar logic is applicable to the limitation that recites a singular amount, e.g., “about 75 mg/m2”, the range can be calculated as follows:
Lower limit:
75
-
0.1
×
75
=
67.5
g
Upper limit:
75
+
0.1
×
75
=
82.5
g
, said limitation is reasonably interpreted as 62.5 mg/m2 to 82.5 mg/m2.
Claim Objections
Claims 14, 16, 23 and 31 are objected to because of the following informalities:
Regarding claim 14, the article “a” recites in the phrase of “a subject with MMR-proficient and/or microsatellite-stable cancer” should be –the--, because “a subject in need thereof” is already established in the preamble. Therefore, using the article “a” instead of “the” is not proper, because said article “a” is used to refer to a subject matter that is not previously introduced.
Regarding claim 16, the term “admninistering” is incorrectly spelled, and should read – administering--.
Regarding claim 23, the term “is” is repeated twice in the same sentence and one of them should be deleted as it appears to be a typographical error.
Regarding claim 31, “platinum-containing chemotherapeutic agent” is missing a proper article –the-- in the front, and should read –the platinum-containing chemotherapeutic agent— so it is clear that it is referring back to the platinum-containing chemotherapeutic agent set forth in claim 14.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 14-17, 19, 21, 23 and 25-37 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for using administering and cisplatin for treating colorectal cancer, pancreatic cancer, or melanoma as the MMR-proficient cancer, does not reasonably provide enablement for the entire scope of administering the full scope of imidazotetrazine chemotherapeutic agent and platinum-containing chemotherapeutic agent for the full scope of treating an MMR-proficient and/or microsatellite-stable cancer to the extent that the term “treating” includes preventing. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and, (8) the quantity of experimentation necessary. All of the Wands factors have been considered and discussed below:
(1, 5) The breadth of the claims and the Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
In the present case, claim 14 recites a method encompasses administering an effective amount of an imidazotetrazine chemotherapeutic agent, and a platinum-containing chemotherapeutic agent to a subject with MMR-proficient and/or microsatellite-stable cancer for treating an MMR-proficient and/or microsatellite-stable cancer. The specification provides special definition to the term “a” to include plural referents (see e.g., [0028]); and special definition to the term “treat” and “treating” to includes eliminating a tumor (or tumor cells), preventing, delaying, or slowing recurrence (rebound) of a cancer/tumor (see e.g., [0076]). Thus, the breadth of the claims is substantial, because it permits independent selection of an imidazotetrazine chemotherapeutic agent and a platinum-containing chemotherapeutic agent to a subject with any type of cancer that is MMR-proficient and/or microsatellite-stable with the intention to treat, or with the intention to prevent one or more of the MMR-proficient and/or microsatellite-stable cancer other than one that the subject currently has. The dependent claims further include administering to the subject an effective amount of an immune checkpoint inhibitor; and performing a test to determine if the subject has a MMR-proficient and/or microsatellite-stable cancer.
The specification provides no working examples demonstrating the administration of an imidazotetrazine chemotherapeutic agent and a platinum-containing chemotherapeutic agent for preventing the MMR-proficient and/or microsatellite-stable cancer. Instead, the examples cluster around the use of temozolomide (also referred to therein as TMZ) and cisplatin (also referred to therein as CDDP) against CT26 colon cancer, Pan02 PD-1 resistant pancreatic cancer, and B16/F10 PD-1 resistant melanoma cell lines; the use of anti PD-1, temozolomide and cisplatin in mice model; and the use of temozolomide, cisplatin and nivolumab for treating patients with MMR-proficient colorectal cancers.
The claimed invention pertains to administering the entire scope of imidazotetrazine chemotherapeutic agent and the entire scope of claimed platinum-containing chemotherapeutic agent to a subject with MMR-proficient and/or microsatellite-stable cancer, thereby treating the MMR-proficient and/or microsatellite stable cancer such that the term “treating” includes preventing. Thus, the nature of the invention therefore depends on whether administering an effective amount of imidazotetrazine chemotherapeutic agent and platinum-containing chemotherapeutic agent can satisfy the method genus of treating the full scope of one or more MMR-proficient and/or microsatellite-stable cancers, including preventing one or more MMR-proficient and/or microsatellite-stable cancer.
(2, 3, 4) The state of the prior art, the level of skill in the art, and the predictability or lack
thereof in the art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the
art would have known, at the time the application was filed, about the subject matter to which the
claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art
refers to the skill of those in the art in relation to the subject matter to which the claimed invention
pertains at the time the application was filed.”
At the time the application was filed, it was well established in the art that microsatellite instability resulting from defects in DNA mismatch repair is remarkably rare in most solid tumors other than colorectal, ovarian and endometrial cancers. Particularly, Lacroix-Triki (Int J Clin Exp Pathol, 2011. Vol. 4(1): 22-31) reports microsatellite instability is a common feature in subsets of colorectal, ovarian and endometrial cancers, and it is remarkably rare in unselected breast cancers (see e.g., abstract). Bloom (“What is microsatellite instability?” [Online]. UT MD Anderson) reports microsatellite instability is much less common for all cancer types other than colon cancer, usually in the low single digits or even less than 1% (see e.g., p. 3, “How does my doctor know if I have MSI? Do I need to ask them to test for it?”, 1st paragraph).
The state of art also demonstrates that the imidazotetrazine chemotherapeutic agent and the platinum-containing chemotherapeutic agent alone are not known to treat the full scope for cancer. Specifically, Neijt et al. (Acta Oncol, 1989. Vol. 28(5): 663-5) reports none of the patients with advanced ovarian cancer responded to the treatment with mitozolomide, an imidazotetrazine (see e.g., p. 665, References, list 2), in Phase II trial and concludes mitozolomide is not active in this patient population (see e.g., abstract); and Trudeu et al. (Ann Oncol, 2006. Vol. 17(6): 952-6) reports while temozolimide demonstrates activity in glioblastoma (see e.g., p. 952, left column, 1st paragraph), no responses to temozolomide were documented in heavily pretreated women with extensive metastatic breast cancer including brain metastases (see e.g., abstract). Delpeuch et al. (Anticancer Res, 2011. Vol. 31(5): 1765-7) also reports oxaliplatin is an anticancer agent only approved for treatment of colorectal cancer, and its off-label use combined either with fluorouracil or gemcitabine in patients with metastatic breast cancer was of little worth given its modest activity and significant toxicity (see e.g., p. 1766, right column, 1st paragraph; abstract; p. 1767, left column, last paragraph); and Wheate et al. (Dalton Trans, 2010. Vol. 39(35):8113-27) reports several platinum(II)-based drugs, such as Spiroplatin and BBR3464, fail to demonstrates activity in Phase II studies(see e.g., Table 2).
The state of the art also demonstrates that pancreatic cancer cannot be prevented. Specifically, American Cancer Society (“Can Pancreatic Cancer Be Prevented?” [Online]) reports there is no sure way to prevent pancreatic cancer; and American Caner Society (“What is Cancer Resurrence?” [Online]) also reports that there is no sure way to prevent cancer from coming back after treatment.
While the art established majority of cancer is microsatellite stable/MMR-proficient and reflects that certain species of imidazotetrazine chemotherapeutic agent and platinum-containing chemotherapeutic agent demonstrates anticancer effect against some types of cancer, the state of the art also demonstrates that some chemotherapeutic agent species of imidazotetrazine chemotherapeutic agent and platinum-containing chemotherapeutic agent are not known to treat certain types of cancer. Thus, the state of the art does not establish a generally applicable rule by which a skilled artisan could select arbitrary species of imidazotetrazine chemo chemotherapeutic agent and platinum-containing chemotherapeutic agent within the present Markush definition and reasonably predict that they would retain the asserted utility of treating the full scope of microsatellite stable/MMR-proficient cancer to the extent that the claimed term “treating” includes preventing, especially armed with the knowledge that cancers and cancer recurrence cannot be prevented.
A person of ordinary skill in the art would likely possess substantial training to conduct experimentation in the field of medicinal chemistry and pharmacology, thereby reducing the difficulty in testing the claimed imidazotetrazine chemotheraeptuic agent and platinum-containing chemotherapeutic agent in a subject in need thereof; However, enablement is not evaluated soley on whether conducting a experiment or clinical trial for treating the full scope of MMR-proficient and/or microsatellite-stable cancer is technically familiar. A skilled artisan’s ability to conduct experiment or clinical trials in a subject does not supply the missing predictive guidance concerning which imidazotetrazine chemotheraeptuic agent and platinum-containing chemotherapeutic agent will possess the disclosed utility of treating the entire scope of MMR-proficient and/or microsatellite-stable cancer, to the extent that the claimed term “treating” includes preventing.
Lastly, the art surrounding the treatment of cancer, including prevention, is highly unpredictable. As noted above, the cited reference noted above demonstrates each imidazotetrazine chemotherapeutic agent and platinum-containing chemotherapeutic agent is not known to treat certain types of cancer; and American Cancer Society demonstrates cancer, such as pancreatic cancer, and cancer recurrence cannot be prevented. Therefore, there is lack of predictability surrounding the treatment of cancer MMR-proficient and/or microsatellite-stable cancer to the extent that the treatment includes preventing. The art would not have reasonable expectation of that combining any imidazotetrazine chemotherapeutic agent and a platinum-containing chemotherapeutic agent would exhibit an universal treatment, including preventive effect, across the broad genus of MMR-proficient and/or microsatellite-stable cancer encompassed by the claims, because one of ordinary skill in the art would be required to conduct extensive search to determine which particular combination, including dosing and route of administration, are predictive for treating the full scope of MMR-proficient and/or microsatellite-stable cancer, including preventing.
(6, 7, 8) The amount of guidance given, the presence of working example and the quantitation
of experimentation required:
In the present case, the specification as-filed describes the invention may directs to treatment of any cancer type in a subject in need thereof, including MMR-proficient and/or microsatellite stable (MSS) cancer (see e.g., [0078]), and further describes imidazotetrazines are a class of bi-cyclic aromatic heterocycles that can include temozolomide (TMZ) and dacarbazine (see e.g., [0068]), and platinum-containing chemotherapeutic agents such as cisplatin, carboplatin, and/or oxaliplatin can be used (see e.g., [0069]), the working examples disclosed therein are clustered around the use of temozolomide and cisplatin.
Particularly, the working examples (see Example 1-2) demonstrate the use of temozolomide and cisplatin against CT26 colon cancer, PD-1 resistant pancreatic cancer (Pan02), and PD-1 resistant melanoma cell (B16/F10); the use of anti PD-1, temozolomide and cisplatin in mice model; and the use of temozolomide, cisplatin and nivolumab for treating patients with MMR-proficient colorectal cancers. Thus, the working examples disclosed therein are also clustered around the treatment of particular MMR-proficient cancers that is insufficient to supply general predictive rule in treating the full scope of MMR-proficient cancers and/or microsatellite-stable cancer to the extent that “treating” includes preventing.
Given the breadth of the claimed genus and the unpredictability of the art surrounding the treatment and prevention of cancer, a skilled artisan would be required to screen numerous untested cancers and untested species of imidazotetrazine chemotherapeutic agent and platinum-containing chemotherapeutic agent to determine which particular combination thereof would successfully treat, including prevent, the MMR-proficient cancers and/or microsatellite-stable cancers. The fact that the specification only provides limited guidance, the task left by the present disclosure is therefore not simply to reproduce the disclosed procedure by replacing cisplatin with another art-recognized platinum-containing chemotherapeutic agent, replacing temozolomide with another imidazotetrazine chemotherapeutic agent for reasonable number of times; Rather, it involves extensive experimentation across exceptionally broad method genus.
Conclusion
A skilled artisan therefore would not be able, based upon the specification and ordinary knowledge alone, to use the full scope of the claims for treating the MMR-proficient cancers and/or microsatellite-stable cancers without undertaking an extensive research program. Accordingly, the experimentation required is not merely routine confirmation of predictable results, it constitutes undue experimentation directed to discovering which particular combinations are operative. Therefore, the entire scope of clamed invention is not enabled by the instant specification
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 14-17, 19, 21, 23 and 25-37 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 claims 14 and 37, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, the claims recite the broad recitation “MMR-proficient”, and the claims also recite “microsatellite-stable”, which is the narrower statement of the range/limitation. It is respectfully noted that the term “MMR-proficient” tumors is recognized in the art to include those that are microsatellite stable (MSS) and microsatellite instability-low (MSI-L) or tumors with intact MMR proteins, according to Sinicrope (Nat Rev Clin Oncol, 2010. Vol. 7(3): 174–177) (see e.g., p. 2, line 14-15). Therefore, to the extent the claim is drawn to MMR-proficient and microsatellite-stable cancer, then it is not clear if the cancer includes other tumors that is not microsatellite stable, such as MSI-L tumnors; and for that instance, it is not clear if there are more than one cancer being treated. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Accordingly, claims 15-17, 19, 21, 23 and 25-37 are rejected based on their dependency on a rejected base claim.
Regarding claims 29, 30 and 33-34, the claims recite the limitation "the" temozolomide; However, temozolomide is not recited prior to said limitation, and it is not clear what is being referred to as “the temozolomide”.
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.
Claims 14-17, 19, 21, 23, 25-29, 32-33, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Stein et al. (WO 2019/200229 A1; cited in the IDS filed on June 20, 2023), in view of NCT03832621 (V2: February 26, 2019; cited in the IDS filed on June 20, 2023) and Pani et al. (Cell Cycle. 2007 Jul 15;6(14):1796-802), as evidenced by Sinicrope (Nat Rev Clin Oncol, 2010. Vol. 7(3): 174–177) and Shi et al. (PloS one, 2013. Vol. 8, 10: e76012).
Please note NCT03832621 (V2: February 26, 2019) is cited in the IDS filed on June 20, 2023; However, the examiner noted that the copy provided by Applicant is partially cropped. Therefore, the Examiner has provided another copy of said reference and cited in the PTO-892 Form, any reference hereinafter to column and line numbers will be based upon the copy provided by the Examiner.
Stein et al. teaches a method of treating a cancer in a subject, the method comprising administering to the subject an anti-PD-L1 antibody molecule at a dose or dosage schedule described therein (see e.g., p. 38, line 32-34); wherein the anti-PD1 antibody molecule is nivolumab (see e.g., p. 120, line 13-14); wherein the cancer is a metastatic colorectal cancer, microsatellite stable colorectal cancer, a mismatch repair proficient colorectal cancer (see e.g., p. 6, line 24-27; p. 7, line 24-32). Stein et al. further teaches the anti-PD-L1 antibody molecule is administered or used in combination with one, two, or all of a chemotherapeutic agent, including a platinum agent, e.g., cisplatin (see e.g., p. 24, line 24-26; p. 21, line 24-26); and other exemplary chemotherapeutic agents that can be used in combination with the anti-PD-L1 antibody molecules include a monofunctional alkylator, e.g., temozolomide (see e.g., p. 21, line 6-9). Stein et al. further teaches the anti-PD-L1 antibody molecule is in combination with a therapeutic agent, procedure, or modality in an amount effective to treat or prevent a disorder (see e.g., p. 19, line 4-9). Stein et al. further teaches the anti-PD-L1 antibody molecule is administered at a dose from about 20 mg to about 2000 mg once every three weeks, once every four weeks, or once every six weeks (see e.g., p. 114, line 30-33). Stein et al. further teaches in a preferred embodiment, the antibody is administered by intravenous infusion or injection (see e.g., p. 104, line 28-30). Stein et al. further teaches the anti-PD-L1 antibody can be administered or used in combination with, one or more of, inter alia, an immunomodulator (e.g., an activator of a costimulatory molecule or an inhibitor of an inhibitory molecule, e.g., an immune checkpoint molecule) (see e.g., p. 20, line1-5).
Stein et al. does not expressly demonstrate administering the elected imidazotetrazine chemotherapeutic agent species (temozolomide) and the elected platinum-containing chemotherapeutic agent species (cisplatin) for treating the elected MMR-proficient cancer (colorectal cancer).
NCT03832621 teaches a Phase II, multicenter, single arm trial designed to evaluate the efficacy and safety of nivolumab (480 mg i.v. every 4 weeks), ipilimumab and temozolomide (TMZ) (150 mg/m2 daily on days 1-5 every 4 weeks) combination in patients with microsatellite stable, O⁶-methylguanine-DNA methyltransferase (MGMT)-silenced metastatic colorectal cancer (CRC) (see e.g., p. 5, “Brief Summary”, 1st paragraph). Please note the microsatellite stable colorectal cancer taught by NCT03832621 is MMR-proficient, as evidenced by Sinicrope (see e.g., p. 2, line 14-15). NCT03832621 further teaches in the inclusion criteria, the enrolled patients have histologically confirmed metastatic or inoperable adenocarcinoma of the colon and/or rectum, with centrally confirmed mismatch repair proficiency (microsatellite stable [MSS]) by multiplex polymerase chain reaction (PCR), MGMT promoter methylation by methylation-specific PCR (MSP) and MGMT low expression by IHC (see e.g., p. 8, “Criteria”, “Inclusion Criteria”, list 8). NCT03832621 further teaches immune checkpoint inhibitor have been shown to trigger durable antitumor effects in a subsect of patients; and early clinical testing demonstrates checkpoint inhibitor may have increased activity in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) tumors whereas mismatch repair-proficient colorectal cancer is unresponsive to immune checkpoint inhibitors (see e.g., p. 6, last paragraph to p. 7, first paragraph). NCT03832621 further teaches previous reports indicate that acquired resistance to temozolomide may emerge through the induction of a microsatellite-instability positive phenotype; and the investigators recently showed that inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models (see e.g., p. 7, 2nd paragraph). NCT03832621 further teaches the investigators hypothesize that treatment of microsatellite stable MGMT hypermethylated CRCs with alkylating agents could reshape the tumor genetic landscape by increasing the tumor mutational burden either directly (by inducing G>A mutations) or/and indirectly (by inactivating DNA repair genes such as MLH1, MSH2 or MSH6, which in turn could lead to hypermutated phenotype) therefore enhancing formation of cancer neoantigens and immunogenicity; TMZ treatment can also modulate the repertoire of immune cells (Tregs, Tc, NK) favoring T cell activation; To achieve potential sensitization to immunotherapy by means of TMZ-induced MSI-like status, treatment with TMZ should be active (i.e. inducing a SD/PR/CR) (see e.g., p. 7, last paragraph to p. 8, line 2). NCT03832621 further teaches temozolomide is an oral prodrug of dacarbazine (see e.g., p. 4, last 2 lines).
Pani et al. teaches a study that evaluates the response of cisplatin in the human colon cancer cell line HCT116 (MMR-deficient), and its hMLH1-proficient subline HCT116+chr3 (MMR‑proficient)(see e.g., p. 1797, left column, “Materials and Methods”, 1st paragraph; abstract; Figure 2); and further teaches apoptosis was evident in both cell lines post-treatment (48-72h) as indicated by the sub‑G1 peak in the flow cytometric profiles and the degradation of cellular proteins such as Cdk1, which is representative of proteins that are expressed throughout the cell cycle (see e.g., left column, line 35-39; Figure 3A-3B). Please note the HCT116 colon cancer cell is colorectal cancer cell line, as evidenced by Shi et al. (see e.g., title).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to modify the method taught by Stein et al. to selectively choose to administer nivolumab as the anti-PD-L1 antibody molecule in combination with temozolomide as the monofunctional alkylator, and cisplatin as the platinum agent for treating a mismatch repair proficient colorectal cancer.
One would have been motivated to do so, because Stein et al. expressly teaches the anti-PD-L1 antibody molecule, including nivolumab, may be administered or used in combination with one, two, or all of a chemotherapeutic agent in an effective amount, including a platinum agent such as cisplatin, and a monofunctional alkylator, e.g., temozolomide, for treating cancer, including a mismatch repair proficient colorectal cancer. Thus, Stein et al. itself would have suggested the skilled artisan to use nivolumab in combination with two other chemotherapeutic agents, cisplatin and temozolomide, in an amount effective for treating a mismatch repair proficient colorectal cancer.
NCT03832621 provides the reason for selecting nivolumab among the anti-PD-L1 antibody molecules, selecting temozolomide among the monofunctional alkylators and combining them together. In particular, NCT03832621 expressly teaches that the combination comprising nivolumab and temozolomide is currently undergoing a Phase II clinical trial to evaluate its efficacy and safety in treating microsatellite stable, MGMT-silenced colorectal cancer; and expressly teaches that alkylating agent temozolomide induces microsatellite instability-like status in microsatellite stable, MGMT-silenced colorectal cancer by increasing immunogenicity and the tumor mutational burden either directly or/and indirectly to achieve potential sensitization to immunotherapy; and immune checkpoint inhibitors have been shown to trigger durable antitumor effects, especially checkpoint inhibitors may have increased activity in dMMR/microsatellite instability-high (MSI-H) tumors.
Pani et al. provides the reason for selecting cisplatin as the platinum agent that can be used in the combination of chemotherapeutic agents. In particular, Pani et al. teaches cisplatin induces cell apoptosis in both MMR‑proficient and MMR-deficient human colon cancer cell line.
Accordingly, in view of Stein et al.’s teachings permitting nivolumab to be used as anti-PD-L1 antibody molecule in combination with more than one chemotherapeutic agent, including cisplatin and temozolomide for treating MMR-proficient colorectal cancer; NCT03832621’s teachings of temozolomide as the alkylating agent for sensitizing the microsatellite stable colorectal cancer, which is MMR-proficient as evidenced by Sinicrope, to immunotherapy by including nivolumab in the combination; and Pani et al.’s teachings of cisplatin as platinum agent useful for both MMR‑proficient and MMR-deficient human colorectal cancer, one of ordinary skill in the art would have had a reason to select temozolomide and cisplatin for incorporation as the chemotherapeutic agents to be used in combination with anti-PD-L1 antibody molecule nivolumab. One woold have a reasonable expectation of success to arrive at the claimed invention, because these agents are individually taught by the prior arts to be useful for the same purpose, and one would have reasonably expected that by combining these agents together at an effective amount, they would have successfully treated MMR-proficient colorectal cancer.
Regarding the limitation of “further comprising performing a test to determine if the subject has a MMR-proficient and/or microsatellite-stable cancer prior to …” in claim 16, it would have been prima facie obvious to one of ordinary skill in the art a the time the application was filed to perform a test to determine whether the patients have mismatch repair proficiency of the colorectal cancer prior to the treatment set forth in the method above. One would have been motivated to do so, because NCT03832621 expressly teaches the Phase II clinical trial, which is testing the combination to treat microsatellite stable colorectal cancer, enrolled patients with centrally confirmed mismatch repair proficiency (microsatellite stable) by multiplex polymerase chain reaction. Thus, performing a test to confirm patients have mismatch repair proficiency prior to treating mismatch repair proficiency colorectal cancer is well-known and routine in the art, because one would have reasonably expected that the test can confirm the subject does have mismatch repair proficiency before the treatment is conducted.
Regarding the limitation of “the cancer is immune checkpoint inhibitor resistant” in claim 19, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to selectively choose to incorporate the cancer that is immune checkpoint inhibitor resistant. One would have been motivated to do so, because NCT03832621 expressly teaches mismatch repair-proficient colorectal cancer is unresponsive to single-agent immune checkpoint inhibitors, but these checkpoint inhibitors may have increased activity in mismatch repair-deficient/microsatellite instability-high tumors; and suggested that alkylating agent temozolomide induces microsatellite instability-like status in microsatellite stable colorectal cancer may achieve potential sensitization to immunotherapy. Accordingly, NCT03832621 itself would have suggested the incorporation of temozolomide and immune checkpoint inhibitors, including nivolumab, together to treat mismatch repair-proficient colorectal cancer that was unresponsive to immune checkpoint inhibitor monotherapy by inducing microsatellite instability-like status to the microsatellite stable colorectal cancer. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the administration of temozolomide in the method set forth above would have successfully induced microsatellite instability-like status, thereby enhancing nivolumab’s antitumor effect.
Regarding the limitation of “immune checkpoint inhibitor is…administered by IV infusion” in claim 28, the limitation of “the nivolumab is administered to the subject by IV infusion about at about 480 mg about every 4 weeks (480 mg Q4W)” in claim 32, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to selectively choose to administer the nivolumab in the method set forth above by intravenous infusion at a dose of 480 mg every 4 weeks. One would have been motivated to do so, because Stein et al. expressly teaches the anti-PD-L1 antibody molecule, including nivolumab, can be administered by intravenous infusion or injection at a dose from about 20 mg to about 2000 mg once every four weeks; and NCT03832621 teaches the nivolumab is administered at 480 mg i.v. every 4 weeks to patients with microsatellite stable, MGMT-silenced colorectal cancer. Accordingly, Stein et al. itself would have suggested intravenous infusion is one of the preferred routes of administering nivolumab intravenously, and NCT03832621 provides the suitable dosing regimen of nivolumab (480 mg every 4 weeks) for treating MMR-proficient colorectal cancer; thus, one would have reasonably chosen to administer the nivolumab at 480 mg by IV infusion every 4 weeks with an expectation that it would treated MMR-proficient colorectal cancer with a reasonable expectation of success.
Regarding the limitations of “wherein the temozolomoide is administered orally” in claim 29, and “wherein the temozolomoide is administered to the subject orally… at about 50-200 mg/m2, day 1-5, about every 4 weeks (Q4W)” in claim 33, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to selectively choose to administer the temozolomide in the method set forth above orally at a dose of 150 mg/m2 daily on days 1-5 every 4 weeks. One would have been motivated to do so, because Stein et al. teaches chemotherapeutic agents can be combined in an effective amount; and NCT03832621 expressly teaches temozolomide is an oral prodrug of dacarbazine, and the temozolomide is administered at a dose of 150 mg/m2 daily on days 1-5 every 4 weeks to patients with microsatellite stable, MGMT-silenced colorectal cancer. Accordingly, NCT03832621 itself would have suggested that temozolomide is an oral drug, and further suggested the dosing regimen of temozolomide (150 mg/m2 daily on days 1-5 every 4 weeks) for treating MMR-proficient colorectal cancer; thus, one would have reasonably chosen to administer the temozolomide orally at 150 mg/m2 daily on days 1-5 every 4 weeks with an expectation that it would treated MMR-proficient colorectal cancer with a reasonable expectation of success.
Regarding the limitations of “the method: (a) enhances the immunogenicity of MMR-proficient and/or microsatellite stable (MSS) cancer cells in the subject…” in claim 37, these limitations express the intended outcome of the positively recited administration steps and do not positively require an additional manipulative method step. See MPEP §2111.04. The claims positively require the administration of the effective amount of the imidazotetrazine chemotherapeutic agent and the platinum-containing chemotherapeutic agent to a subject in need thereof. The method made obvious by the prior arts set forth above includes the administration of temozolomide and cisplatin at an effective amount. Particularly, in view of the NCT03832621’s expressive teaching of temozolomide for enhancing immunogenicity and sensitizing the microsatellite stable colorectal cancer to immunotherapy, one would have reasonably expected that the administration of temozolomide would have successfully enhanced the immunogenicity and/or enhancing the sensitivity of the MMR-proficient colorectal cancer cell. Accordingly, the recitation of the intended treatment outcome does not distinguish the claimed method from the method made obvious by the prior arts set forth above.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 14-17, 19, 21, 23, 25-29, 31-33 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Stein et al. (WO 2019/200229 A1; cited in the IDS filed on June 20, 2023), in view of NCT03832621 (V2: February 26, 2019) and Pani et al. (Cell Cycle. 2007 Jul 15;6(14):1796-802) as applied to claims 14-17, 19, 21, 23, 25-29, 32-33, and 37 above, and further in view of Abra et al. (US 5,945,122 A) and Cutler et al. (US 2003/0185831 A1).
The teachings of Stein et al., NCT03832621, and Pani et al. are set forth above and applied as before.
Stein et al., NCT03832621, and Pani et al. does not teach the elected platinum-containing
chemotherapeutic agent (cisplatin) is administered by IV infusion as claimed in claim 31. Stein et al., NCT03832621, and Pani et al. also does not teach the cisplatin is administered to the subject by IV infusion at about 60 to 100 mg/m2 every 3 to 4 weeks as claimed in claim 35.
Abra et al. teaches cisplatin is available as a sterile aqueous solution and in this form is typically administered intravenously for tumor therapy at a dose of between about 20-120 mg/m2; the drug may be administered alone or in combination with other chemotherapeutic agents, as a bolus injection or as a slow infusion over a period of several hours (see e.g., Col. 7, line 13-20). Abra et al. further teaches as a single agent, cisplatin can be administered, for example, at a dose of 100 mg/m2 intravenously once every 4 weeks or at a dose of 20 mg/m2 cisplatin given as rapid intravenous infusion daily for 5 days and repeated at 4-week intervals; and in treatment of squamous cell cancer of the head and neck, cisplatin given intravenously as a 24-hour infusion at a dose of 80 mg/m2 achieved favorable response (see e.g., Col. 2, line 21-29). While active as a single agent, cisplatin is often administered in combination with other agents, for examples, therapy of ovarian cancer may include 60 mg/m2 cisplatin and 60 mg/m2 adriamycin administered as a 24-hour infusion (see e.g., Col. 7, line 30-40).
Culter et al. teaches the antineoplastic agents used with the FPT inhibitor are administered in their normally prescribed dosages during the treatment cycle (i.e., the antineoplastic agents are administered according to the standard of practice for the administration of these drugs), for example, about 30 to about 100 mg/m2 for cisplatin (see e.g., [0233]). Culter et al. further teaches antineoplastic agent could be given by bolus or continuous infusion; the antineoplastic agent could be given daily to once every week, or once every two weeks, or once every three weeks, or once every four weeks during the treatment cycle (see e.g., [0230]). Culter et al. further teaches the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated; determination of the proper dosage for a particular situation is within the skill of the art (see e.g., [0358]).
Regarding claim 31, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to selectively choose to administer the cisplatin in the method set forth above by IV infusion. One would have been motivated to do so, because Abra et al. teaches cisplatin is available as a sterile aqueous solution suitable that is typically administered intravenously as a slow infusion over a period of several hours. Accordingly, Abra et al. itself would have suggested that intravenous infusion is one of the suitable routes for administering commercially available cisplatin; thus, one of ordinary skill in the art would have reasonably choose to administer cisplatin by intravenous infusion with an expectation that this route of administration would successfully deliver said drug to the subject in need thereof.
Regarding claim 35, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to selectively choose to administer the cisplatin in the method set forth above by IV infusion at a dose of 100 mg/m2 intravenously once every 4 weeks. One would have been motivated to do so, because Abra et al. teaches cisplatin is known to be administered at a dose of 100 mg/m2 intravenously once every 4 weeks for tumor therapy; and Culter et al. teaches the antineoplastic agents used with another therapeutic agent are administered in their normally prescribed dosages during the treatment cycle. Accordingly, one of ordinary skill the art seeking to administer cisplatin to a subject with mismatch repair-proficient colorectal cancer that falls within the same field of tumor therapy would have had a reason to select a known dosing regimen effective for exhibiting anti-tumor activity as taught by Abra et al. (100 mg/m2 intravenously once every 4 weeks) for incorporation as the effective amount of cisplatin taught by Stein et al. in the combination, thereby, arriving at the claimed invention with a reasonable expectation of success.
Regarding claim 36, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to selectively choose to administer the cisplatin in the method set forth above by IV infusion at a dose of 100 mg/m2 once every 4 weeks. One would have been motivated to do so, because Abra et al. teaches cisplatin is known to be administered at a dose of 100 mg/m2 intravenously once every 4 weeks for tumor therapy. Accordingly, one of ordinary skill the art seeking to arrive at the dose of cisplatin for treating mismatch repair-proficient colorectal cancer, which falls within the same field of tumor therapy, would have had a reason to select a known dosing regimen effective for exhibiting anti-tumor activity taught by Abra et al. for incorporation as the effective amount of cisplatin taught by Stein et al., thereby, arriving at the claimed invention with a reasonable expectation of success.
Regarding claim 37, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to selectively choose to administer the cisplatin in the method set forth above by IV infusion at a dose of 20 mg/m2 daily, and then optimizing said dose through routine optimization thereby arriving at the claimed dose . One would have been motivated to do so, because Abra et al. teaches the dose of cisplatin is typically between 20-120 mg/m2, and said drug is known to be administered at a dose of 20 mg/m2 as an intravenous infusion daily for tumor therapy; and Culter et al. teaches the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Thus, Culter et al. itself established that the dose of cisplatin was a known result-effective and routinely adjustable parameter. Accordingly, one of ordinary skill the art seeking to arrive at the dose of cisplatin starting from a known dosing regimen as taught by Abra et al. (20 mg/m2 cisplatin given as rapid intravenous infusion daily) for treating mismatch repair-proficient colorectal cancer, which falls within the same field of tumor therapy, would have had a reason to optimize said dose based on the severity of the cancer within the known workable range of 20-120 mg/m2, thereby, arriving at the claimed dose with a reasonable expectation of success.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 14-17, 19, 21, 23, 25-30, 32-34, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Stein et al. (WO 2019/200229 A1; cited in the IDS filed on June 20, 2023), in view of NCT03832621 (V2: February 26, 2019) and Pani et al. (Cell Cycle. 2007 Jul 15;6(14):1796-802) as applied to claims 14-17, 19, 21, 23, 25-29, 32-33, and 37 above, and further in view of Abutarif et al. (US 2010/0210700 A1).
The teachings of Stein et al., NCT03832621, and Pani et al. are set forth above and applied as before.
Stein et al., NCT03832621, and Pani et al. does not teach the temozolomoide is administered by IV infusion as claimed in claim 30. Stein et al., NCT03832621, and Pani et al. also does not teach the temozolomoide is administered to the subject by IV infusion at about 75 mg/m2 daily as claimed in claim 34.
Abutarif et al. teaches methods and drug products for treating proliferative disorders using intravenous formulations comprising temozolomide over a specific infusion time; and teaches they are particularly well-suited for patients who cannot swallow oral formulations (see e.g., abstract); wherein the proliferative disorder is selected from, inter alia, colorectal cancer (see e.g., [0012]). Abutarif et al. further teaches the formulation is designed for administration by intravenous infusion over a period of about 1 hour to about 2 hours (see e.g., [0016]); and in some embodiments, the formulation is administered at a dose of 75 mg/m2 per day for 42 consecutive days (see e.g., [0025]).
Regarding claim 30, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to selectively choose to administer the temozolomide in the method set forth above by IV infusion. One would have been motivated to do so, because Abutarif et al. teaches an intravenous formulation comprising temozolomide that is particularly well-suited for patients who cannot swallow oral formulation; and further teaches said formulation can be administered by intravenous infusion over a period of about 1 hour to about 2 hours. Accordingly, Abutarif et al. itself would have suggested that intravenous infusion is one of the alternative routes for administering temozolomide. Thus, one of ordinary skill in the art would have reasonably choose to administer temozolomide by intravenous infusion with an expectation that this route of administration would successfully deliver said drug to the subject in need thereof that cannot swallow oral formulation.
Regarding claim 34, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to selectively choose to administer the temozolomoide in the method set forth above by IV infusion at a dose of 75 mg/m2 per day. One would have been motivated to do so, because Abutarif et al. teaches an intravenous formulation comprising temozolomide that can be administered by intravenous infusion at a dose of 75 mg/m2 per day for treating proliferative disorder, including colorectal cancer. Accordingly, one of ordinary skill the art seeking to administer temozolomoide to a subject with mismatch repair-proficient colorectal cancer that falls within the same field of colorectal cancer would have had a reason to select a known IV infusion dosing regimen effective as taught by Abutarif et al. (75 mg/m2 per day) for incorporation as the effective amount of temozolomide taught by Stein et al. in the combination, thereby, arriving at the claimed invention with a reasonable expectation of success.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chihyi Lee whose telephone number is (571)270-0663. The examiner can normally be reached Monday - Friday 8:30 am - 5:00 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L. Clark can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
