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 .
Priority
The instant application is a 35 U.S.C. § 371 national stage filing of No. PCT/US2022/022592, filed on March 30, 2022, which claims the benefit of the U.S. provisional application No. 63/168,896, filed March 31, 2021.
Application and Claims Status
Claims 1, 3, 6, 10, 12, 18, 20, 24, 27, 30, 33, 37, 46, 50, 56, 59, 63-64, and 88-89 are pending. In the amendment as filed on September 29, 2023, applicants have amended claims 3, 6, 10, 12, 18, 20, 24, 27, 30, 33, 37, 46, 50, 56, 59, 63-64, and 88-89; cancelled claims 2, 4-5, 7-9, 11, 19, 21-23, 25-26, 28-29, 34-36, 38-45, 47-49, 51-55, 57-58, 60-62, 65-87, 90-105; and added no new claims.
Information Disclosure Statement
The information disclosure statement (IDS) filed on February 11, 2025 is in compliance with the provisions of 37 CFR 1.97. All references have been considered except where marked with a strikethrough. A signed copy of Form 1449 is included with this Office Action.
Abstract
Applicant is reminded of the proper content of an abstract of the disclosure.
The abstract of the disclosure does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b). A new abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text.
In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics.” Exemplification of a species could be illustrative of members of the class. For processes, the type of reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary.
The abstract of the disclosure is objected to because: it does not commence on a separate sheet in accordance with 37 CFR 1.52(b)(4) and 1.72(b); it does not comment on the intended therapeutic use of claimed compounds. Correction is required. See MPEP § 608.01(b).
The examiner suggests presenting the abstract on a separate sheet, apart from any other text, and including the intended therapeutic use of claimed compounds.
Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any of the errors of which applicant may become aware of in the specification.
Claim Objections
Claim 46 is objected to because of the following informality: in the currently amended claim, there are two periods at the end of the claim where Applicant inserted new text. There should only be a single period. Appropriate correction is required.
Claim 63 is objected to because of the following informality: in the currently amended claim, there are two commas at the end of the phrase where Applicant inserted new text of “or a pharmaceutically acceptable salt thereof” when there should only be a single comma. 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.
Scope of Enablement - Compounds
Claims 1, 3, 6, 10, 12, 18, 20, 24, 27, 30, 33, 37, 46, 50, 56, 59, 63, and 64 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 the following:
A compound having a structure of Formula I (as recited in claim 1)
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or a pharmaceutical composition comprising a compound having a structure represented by Formula I (as recited in claim 64):
wherein R16, R17, and R18 is absent, m = 0
wherein R1 is -C(CR4)2)nR5, where, where R5 is phenyl or cyclopropyl, R5’ is halo, R4 is hydrogen, and n= 0, 1
wherein R2 is phenyl, R7 and Y is as defined in claim 20, R8 is hydrogen, R10 is hydrogen, R9 is hydrogen, R9’ is hydrogen, alkyl, haloalkyl, heteroalkyl, or (alkyl)heterocyclcoalkyl.
wherein R3 is pyrazolyl, pyridyl, phenyl, heterocycloalkyl, cycloalkyl, R12 is halo, alkyl, heteroalkyl, and R13, R14, and R15 are absent
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention:
The nature of the invention relates to compounds of Formula I in claim 1. Such compounds are useful for treating cancers with EGFR mutations. This invention is also directed to compositions comprising said compounds.
Predictability of the art:
The compounds synthesized in the instant specification appear novel. However, the hypothetical compounds in claim 1 would be unpredictable in terms of one skilled in the art being able to synthesize every possible compound claimed in instant claim 1. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Level of skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing and screening chemical compounds for particular activities, such as a medical doctor or chemist. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems.
The breadth of the claims:
The scope of the claims involves compounds of Formula I:
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and a pharmaceutical composition comprising the compound represented by Formula 1. Claim 1 is very broad in the number of variables and the options of substituents for each variable. There is an extremely large amount of hypothetical compounds included in claim 1.
The amount of direction provided, the presence or absence of working examples, and the quantity of experimentation necessary:
The specification only provides the synthesis of 45 compounds.
Synthesis methods are not taught in the specification to provide for the aforementioned variables to include all of the possible substituents listed in the claims. For example, there are no working examples of a compound of Formula I wherein there is an R16 group along the diazepanone-fused pyrimidine core. Additionally, it would be expected that R10 substitution of the nitrogen (e.g., alkyl, haloalkyl, and cycloalkyl) and R2 rings others than phenyl would change the reactivity of the compounds, and therefore may require alternate synthesis methods. It would require one skilled in the art, such as a chemist, to perform thousands of reactions to determine which compounds of Formula I can be prepared and would likely require synthesis methods other than those provided in the specification. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claims 3, 6, 10, 12, 18, 20, 24, 27, 30, 33, 37, 46, 50, 56, 59, 63, and 64, which are dependent on claim 1, are also rejected for further requiring and/or reciting elements that are outside the scope of the enabling elements listed above.
Scope of Enablement – Cancer
Claims 88-89 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 the treatment of cancers having mutated or aberrant EGFR activity, does not reasonably provide enablement for all forms of cancer as generically embraced by the claim language. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, "The Federal Circuit has repeatedly held that "the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation." In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)" (emphasis added). The "make and use the full scope of the invention without undue experimentation" language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: "A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc., 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int'l, Inc. v. BMWofN. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick y. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor or joint inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. {See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986); and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988)}.
The nature of the invention and breadth of the claims:
The claims are directed towards a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Claim 1. These compounds are inhibitors of different mutants of EGFR as shown through Example 2, where the compounds of the invention were tested in Ba/F3 cells expressing different EGFR mutations. Thus, the claims are directed to a method which can be used to treat all forms of cancer using the compounds of the invention to inhibit mutant forms of EGFR.
The state of the prior art and the predictability or unpredictability of the art:
Thomas (Frontiers in Oncology, August 2019, Volume 9, Article 800) provided a review of the epidermal growth factor receptor (EGFR) in cancer and current treatments targeting this receptor. EGFR is one of the most potent oncogenes that is commonly altered in cancers, and its activity has been serving as the primary target for developing cancer therapeutics. EGFR inhibitors have produced impressive therapeutic benefits to responsive types of cancers. However, acquired and innate resistances have precluded current anti-EGFR agents from offering sustainable benefits to initially responsive cancers and benefits to EGFR-positive cancers that are innately resistant (Abstract). Table 1 (Page 2) lists the cancers which commonly possess alterations of EGFR, and the current status of tyrosine kinase inhibitors in their treatment. As of publication, the only two forms of cancer of the 13 that are listed that are currently treated using tyrosine kinase inhibitors are non-small cell lung cancer and pancreatic, with marginal efficacy noted in pancreatic cancer. The authors state that this is due to the prevalence of mutations in those forms of cancer (Page 3). Murtuza (Cancer Research, 2019, 79 (4): 689-698) provides a review of EGFR-activating mutations in non-small cell lung cancer. Approximately 15-20% of patients with NSCLC have an EGFR-activating mutation. Currently there are several third-generation compounds which are at various stages of development for the treatment of EGFR-mutant NSCLC (Abstract). In view of these teachings, inhibition of EGFR can be used to treat certain cancers which possess aberrant EGFR activation, expression or activity. However, not all cancers possess aberrant EGFR activation or expression, and there is currently no known treatment that can be used to treat all forms of cancer.
No single drug has been discovered that is effective in treating the myriad of tumors or cancers, including, but not limited to, bladder cancer, prostate cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, lung cancer, and non-small cell lung cancer. See In re Hokum, 226 USPQ 353 (ComrPats 1985). Since this assertion is contrary to what is known in medicine, proof must be provided that this revolutionary assertion has merits. The existence of such a “compound” is contrary to our present understanding of oncology. Cecil Textbook of Medicine states, “each specific type has unique biologic and clinical features that must be appreciated for proper diagnosis, treatment and study” (see the enclosed article, page 1004). Different types of cancers affect different organs and have different methods of growth and harm to the body.
Those of skill in the art recognize that in vitro assays and or cell-cultured based assays are generally useful to observe basic physiological and cellular phenomenon such as screening the effects of potential drugs. However, clinical correlations are generally lacking. The greatly increased complexity of the in vivo environment as compared to the very narrowly defined and controlled conditions of an in- vitro assay does not permit a single extrapolation of in vitro assays to human diagnostic efficacy with any reasonable degree of predictability. In vitro assays cannot easily assess cell-cell interactions that may be important in a particular pathological state. Furthermore, it is well known in the art that cultured cells, over a period time, lose phenotypic characteristics associated with their normal counterpart cell type. (Freshney, Culture of Animal Cells, A Manual of Basic Technique, Alan R. Liss, Inc., 1983, New York, p4) teach that it is recognized in the art that there are many differences between cultured cells and their counterparts in vivo. These differences stem from the dissociation of cells from a three-dimensional geometry and their propagation on a two-dimensional substrate. Specific cell interactions characteristic of histology of the tissue are lost. The culture environment lacks the input of the nervous and endocrine systems involved in homeostatic regulation in vivo. Without this control, cellular metabolism may be more constant in vitro but may not be truly representative of the tissue from which the cells were derived. This has often led to tissue culture being regarded in a rather skeptical light (p. 4, see Major Differences In Vitro). Further, although drawn specifically to cancer cells, Dermer (Bio/Technology, 1994, 12:320) teaches that, "petri dish cancer" is a poor representation of malignancy, with characteristics profoundly different from the human disease. Further, Dermer teaches that when a normal or malignant body cell adapts to immortal life in culture, it takes an evolutionary type step that enables the new line to thrive in its artificial environment. This step transforms a cell from one that is stable and differentiated to one that is not. Yet normal or malignant cells in vivo are not like that. The reference states that evidence of the contradictions between life on the bottom of a lab dish and in the body has been in the scientific literature for more than 30 years. Clearly it is well known in the art that cells in culture exhibit characteristics different from those in vivo and cannot duplicate the complex conditions of the in vivo environment involved in host-tumor and cell-cell interactions.
The relative skill of those in the art:
The artisan would generally have an advanced degree related to the treatment or study of various cancers; however, their high level of training and knowledge would not be sufficient to overcome the lack of understanding of how to use the claimed compounds to treat all forms of cancer, as not all forms of cancer develop due to aberrant EGFR activation, nor are all forms of cancer sensitive to inhibition of EGFR for treatment.
The amount of direction or guidance presented and the presence or absence of working examples:
Example 2 (Page 102) and Table 1 (Paragraph 0233) shows each compound of the invention and their ability to inhibit wild type EGFR (A431) and four mutants, showing low activity against wild type, and enhanced inhibitory activity against the mutants which were tested. Thus, the claims provide enablement for the treatment of cancers possessing EGFR mutations, but does not provide any data demonstrating the treatment of cancers which do not possess EGFR mutations.
Representative examples of such a structurally diverse compounds generically embraced in the invention are not shown to possess in vitro activity much less in vivo uses claimed herein. Instant genus embraces compounds bearing a plethora substituents with diverse functional groups and other groups permitted at instant variable groups noted above. There is no reasonable basis for assuming that the myriad of compounds embraced by the claims will all share the same bioactivity profile since they are so structurally dissimilar as to be chemically non- equivalent and there is no basis in the prior art for assuming the same. Note In re Surrey 151 USPQ 724 regarding sufficiency of disclosure for Markush group. Also see MPEP 2164.03 for enablement requirements in cases directed to structure-sensitive art such as the pharmaceuticals. There is insufficient disclosure to reasonably conclude that the method of treating cancer in a subject in need thereof, comprising administering a compound of Formula I, as recited, would contribute to treatment of any the aforementioned diseases. The inventor or joint inventor has neither provided convincing data for any patient population, nor indicated any art recognized correlation between the disclosed data and the breadth of the claim.
The quantity of experimentation necessary:
One skilled in the art, such as a medical doctor, would be required to perform hundreds of clinical trials and in vivo or in vitro assays in order to determine which of the infinite number of compounds of general Formula I would be capable of treating which cancers mediated by EGFR. Even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404. These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Considering the state of the art as described above, in particular with regards to the lack of a panacea for the treatment of cancer due to the heterogenous nature of the disease, and the high unpredictability of the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened.
Scope of Enablement - Prevention
Claims 88-89 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AlA), first paragraph, because the specification, while being enabling for treatment, does not reasonably provide enablement for prevention. 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.
The following Wands factors have been considered if not explicitly discussed: (A) The breadth of the claims, (B) The nature of the invention, (C) The state of the prior art, (D) The level of one of ordinary skill, (E) The level of predictability in the art, (F) The amount of direction provided by the inventor, (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Of particular note, the specification does not provide any definition of “treatment” or “treating” so the Merriam- Webster dictionary definition 1, c of “treatment” was employed, which is defined as “the action or way of treating a patient or condition medically or surgically: management and care to prevent, cure, ameliorate, or slow progression of a medical condition.” Furthermore, while the Applicant does not formally define “treatment” in the instant specification, Applicant does use “treatment, prevention, or suppression of diseases” (Page 13, Paragraph 0053) in the same sentence as synonyms and so the term “treatment” also embraces “prevention.”
It is presumed “prevention” of the claimed condition would require a method of identifying those individuals who will develop the claimed condition before they exhibit symptoms.
The factors to be considered in making an enablement rejection were summarized above. 1) Preventing diseases requires identifying those patients who will acquire the condition before the symptoms occur. This would require extensive and potentially open-ended clinical research on healthy subjects. 2) There is no working example of such a preventive procedure in man or animal in the specification. 4) The claims rejected are drawn to clinical pharmacology and are therefore physiological in nature. 5) The state of the art is that no general procedure is art-recognized for determining which patients generally will develop cancer before the fact. 6) The artisan using Applicants invention would be a Board Certified physician. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of cancer. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable for any agent to be able to prevent cancer. 7) It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved" and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed conditions.
As claims 89 depend upon claim 88, it is also rejected.
Closest Prior Art
Venkateshappa et al (US 2023/0027026 ) disclose compounds of Formula I below, wherein the claimed X and R1, R2, and R3 groups can have overlapping substituents with X and R1, R2, and R3 of the instant application. The difference, of course, is that the instant application is a one-carbon ring-expanded homolog of the fused system to make a diazepanone-pyrimidine core.
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Conclusion
All claims are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUKE ALAN BORALSKY whose telephone number is (571)272-9746. The examiner can normally be reached Monday - Friday 7:30 am - 5:00 am.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey H Murray can be reached at 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.A.B./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624