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 .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 27, 2026 has been reviewed by the examiner and entered of record in the file.
3. Claims 1, 4-6, 8, 10-12, 17-21 and 44 are amended. No claim is canceled or added.
Status of the Claims
4. Claims 16-17 and 20-22, drawn to a kit and a pharmaceutical composition thereof, remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, with traverse, there being no allowable generic or linking claim.
5. Applicant previously elected the species of (1) the telemerase inhibitor: imetelstat or imetelstat sodium; (2) the Bcl-2 inhibitor: ABT-199; and (3) the cancer to be treated: acute myeloid leukemia. Claims 1, 3-13, 15, 18, 19, and 42-46 read on the elected species.
6. The non-elected species remain withdrawn from consideration with traverse.
7. Claims 1, 3-13, 15, 18, 19, and 42-46 are under examination with the elected species and are the subject of this office action.
Previous Claim Rejections - 35 USC § 103
8. Claims 1, 3, 4, 7-13, 15, 18 and 42-46 were previously rejected under 35 U.S.C. 103 as being unpatentable over Kuo et al., Cell Stem Cell (2014), as evidenced by PubChem (https://pubchem.ncbi.nlm.nih.gov/compound/Imetelstat-sodium 2014), further in view of Konapleva et al., Blood (2014).
9. In view of Applicant’s amendments to the claim to incorporate the limitation of dosage amount of the telomerase inhibitor into claims 1 and 18, the previous obviousness rejection is withdrawn. However, upon further consideration, please refer to the following newly applied obviousness rejection, below.
New Claim Rejections - 35 USC § 112(b)
10. 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.
11. Claims 1, 3-13, 18, 19, and 42-46 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.
12. Claim 1 recites the limitation: "…administering a telomerase inhibitor and a Bcl-2 inhibitor in combination to a subject in need thereof,” in lines 2-3, however there is insufficient antecedent basis for this limitation in the claim because the preamble of the claim recites a method of treating a disorder rather than a subject. That is, the preamble fails to recite a method of treating a subject in need of treatment. It is recommended that the preamble be amended to recite: “[a] method of treating a hematological cancer in a subject in need thereof, the method comprising:…”.
13. Claims 3-13, and 42-43 are rejected as being dependent upon and including all of the limitations of claim 1.
14. Claim 18 recites the limitation "…administering imetelstat or a pharmaceutically acceptable salt thereof and a ABT-199 or a pharmaceutically acceptable salt thereof to a subject having acute myeloid leukemia" in lines 2-3, however there is insufficient antecedent basis for this limitation in the claim because the preamble of the claim recites a method of treating a disorder rather than a subject. That is, the preamble fails to recite a method of treating a subject in need of treatment. It is recommended that the preamble be amended to recite: “[a] method of treating acute myeloid leukemia in a subject in need thereof, the method comprising:…”.
15. Claims 19 and 44-46 are rejected as being dependent upon and including all of the limitations of claim 11.
New Claim Rejections - 35 USC § 112(a)
16. 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.
17. Claims 1, 3-13, 42, and 43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In particular, support cannot be found for the full scope of telomerase inhibitors and Bcl-2 inhibitors, as instantly claimed.
18. The MPEP §2163 states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. In the case of chemical entities, Applicant's attention is further directed to Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089, 118 S. Ct. 1548 (1998), which notes that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, “not a mere wish or plan for obtaining the claimed chemical invention.” While the court recognizes that, “[i]n claims involving chemical materials, generic formulae usually indicate with specificity what the generic claims encompass” (Id.), it is also recognized that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim and/or the genus must be sufficiently detailed to show that applicant was in possession of the claimed invention as a whole (see Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555 (Fed. Cir. 1991)). If a genus has substantial variance, the disclosure must present a sufficient number of representative species that encompass the genus in order to adequately describe the genus (i.e., the disclosure must describe a sufficient variety of species to reflect the variation within that genus). See MPEP § 2163. Otherwise, as stated by the court in Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company (Fed. Cir. 2010), “a generic claim may define the boundaries of a vast genus of chemical compounds, and yet the question may still remain whether the specification, including original claim language, demonstrates that the applicant has invented species sufficient to support a claim to a genus.
19. In the instant case, it is evident that the genuses of compounds embraced by both “telomerase inhibitor” and “Bcl-2 inhibitor” has substantial variance. The class of telomerase inhibiting compounds recited by claim 1 embraces any compound that specifically targets the telomerase enzyme, which bear little structural resemblance to one another, including the compounds: imetelstat, BRACO19, BIBR1532, 2′-O-methyl RNA, MST-312, MST-199, and some peptide nucleic acids.
20. The class of Bcl-2 inhibiting compounds recited by claim 1 embraces any compound that specifically targets and neutralizes the activity of B-cell lymphoma 2 (Bcl-2) proteins, which bear little structural resemblance to one another, including the compounds Venetoclax (ABT-199), Navitoclax, Kanglaite, R-(-)-gossypol acetic acid, lisaftoclax, sonrotoclax, AZD-0466, FCN-338, Pelcitoclax, and TQB-3909.
21. However, the Specification discloses the administration of the specific combination of the telomerase inhibitor imetelstat sodium, and the Bcl-2 inhibitor Venetoclax (ABT-199), at certain concentrations in Examples 1-5 in the Specification and Figures 1B, 2B, 5B, and 6B. The instant Specification fails to disclose any other compound species of telomerase inhibitor or Bcl-2 inhibitor.
22. While the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad generic. For example, in In re Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d 1008 (Fed. Cir. 1989). In the instant case, it is similarly determined that the instant disclosure does not adequately describe a subgenus embracing hundreds of thousands of additional compound species bearing no structural relationship. That is, the Specification does not disclose a sufficient variety of species to reflect the extreme variance in the genus.
23. The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate”). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of Formula (I) recited in the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
As such, claims 1, 3-13, 42, and 43 are rejected.
24. Claims 1, 3-13, 42, and 43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating the hematological disorder acute myeloid leukemia in a subject in need thereof, or inducing apoptosis in an acute myeloid leukemia cell, comprising administering a therapeutically effective amount of the combination of imetelstat sodium and Venetoclax (ABT-199) to a subject in need thereof, is not considered enabled for treating the full scope of hematological disorders or inducing apoptosis in any hematological cancer cell, comprising administering any telomerase inhibiting compound and any Bcl-2 inhibiting compound, as presently recited. 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.
25. The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below:
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.
26. 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.
27. 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 instant case, the claims are drawn to a method of treating any/ all hematological disorder(s), or inducing apoptosis in any hematological cancer cell, comprising administering any telomerase inhibiting compound and any Bcl-2 inhibiting compound to a subject in need thereof, wherein the telomerase inhibitor is administered at a dose of about 0.5 mg/kg to 30 mg/kg, and the Bcl-2 inhibitor is administered at a dose of about 50 to 400 mg.
28. The state of the prior art, level of predictability and relative skill level: 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.”
As discussed above, the instantly claimed invention pertains to a method of treating any/ all hematological disorder(s), inducing apoptosis in any hematological cancer cell, comprising administering any telomerase inhibiting compound and any Bcl-2 inhibiting compound to a subject in need thereof, wherein the telomerase inhibitor is administered at a dose of about 0.5 mg/kg to 30 mg/kg, and the Bcl-2 inhibitor is administered at a dose of about 50 to 400 mg.
29. The relative skill of those in the art is high, that of an MD or PhD. That factor is outweighed, however, by the unpredictable nature of the art. As illustrative of the state of the art, Cleveland Clinic teaches that hematological disorders (blood disorders) encompass a wide range of conditions affecting the red blood cells, white blood cells, platelets, and clotting factors, including autoimmune disorders and cancers, wherein said disorders are often complex and unpredictable, can be inherited or acquired, with some requiring lifelong management (webpage printout of Blood Disorders: Types, Symptoms & Treatments, 2022). Cleveland Clinic teaches examples of clotting disorders including Prothrombin gene mutation, Antiphospholipid syndrome, Protein S deficiency, Protein C deficiency, Antithrombin deficiency, Paroxysmal nocturnal hemoglobinuria and Disseminated intravascular coagulation (DIC) (page 2). Cleveland Clinic teaches that bleeding disorders include Von Willebrand disease, hemophilia, thrombocytopenia, and Fibrinogen deficiency conditions; and that disorders affecting red blood cells include Pernicious anemia, Iron-deficiency anemia, Megaloblastic anemia, Aplastic anemia, Autoimmune hemolytic anemia, Macrocytic anemia, Normocytic anemia, sickle cell anemia, Fanconi anemia, Diamone-Blackfan anemia, Thalessemia, hemolytic anemia, sideroblastic anemia, and microcytic anemia (pages 2-3). Cleveland Clinic teaches that blood cancers include leukemia, lymphoma, and myeloma, as well as myeloproliferative neoplasms and myelodysplastic syndromes (page 9).
30. The state of the art regarding treatment of a hematological disorder is that
treatment options for blood disorders are specific to each disorder and include blood factor infusion therapy, blood transfusion therapy, stem cell transplantation, immunotherapy, and/or gene therapy. Cleveland Clinic teaches that common medications for blood disorders include anticoagulants (blood thinners), iron supplements & chelation therapy (i.e., treats iron-deficiency anemia and prevents iron overload in frequent transfusion patients), Erythropoiesis-Stimulating Agents (ESAs) (stimulates red blood cell production in anemia patients), hydroxyurea (reduces sickle cell crises and transfusion dependency in sickle cell disease), corticosteroids, and immunosuppressants (help manage autoimmune blood disorders like immune thrombocytopenia (ITP)) (pages 5-6).
31. The amount of direction or guidance provided and the presence or absence of working examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the specification provides no direction or guidance for the use of the full scope of the aforementioned telomerase inhibitors in combination with the full scope of Bcl-2 inhibitors for the treatment of all recited hematological disorders. The Specification discloses the in vitro activity of only imetelstat sodium and ABT-199 in combination. The Specification has demonstrated evidence that establishes greater than additive results in the treatment of AML tumor cell lines following the administration of the specific combination of imetelstat sodium and ABT-199 at certain concentrations in Examples 1-5 in the Specification and Figures 1B, 2B, 5B, 6B and 16. No reasonably specific guidance is provided concerning useful therapeutic protocols for treating any subject with any hematological disorder comprising administering any other telomerase inhibitor compound(s) or other Bcl-2 inhibitor(s).
32. The breadth of the claims: As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation.” Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, 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 (Fed. Cir. 1993) (emphasis added). At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
33. Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims." Amgen, Inc., v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
34. As to the first inquiry, as discussed above, it is evident that the genuses of compounds embraced by both “telomerase inhibitor” and “Bcl-2 inhibitor” has substantial variance. The class of telomerase inhibiting compounds recited by claim 1 embraces any compound that specifically targets the telomerase enzyme, which bear little structural resemblance to one another, including the compounds: imetelstat, BRACO19, BIBR1532, 2′-O-methyl RNA, MST-312, MST-199, and some peptide nucleic acids. The class of Bcl-2 inhibiting compounds recited by claim 1 embraces any compound that specifically targets and neutralizes the activity of B-cell lymphoma 2 (Bcl-2) proteins, which bear little structural resemblance to one another, including the compounds Venetoclax (ABT-199), Navitoclax, Kanglaite, R-(-)-gossypol acetic acid, lisaftoclax, sonrotoclax, AZD-0466, FCN-338, Pelcitoclax, and TQB-3909.
35. Considering that the scope of each class of compounds encompasses hundreds of thousands of compound species, and potentially millions of compound species, it is evident that the claims are broad. Yet, as discussed above, the instant Specification discloses the administration of just one compound species in each class: the specific combination of the telomerase inhibitor imetelstat sodium, and the Bcl-2 inhibitor Venetoclax (ABT-199), at certain concentrations in Examples 1-5 in the Specification and Figures 1B, 2B, 5B, and 6B. The instant Specification fails to disclose any other compound species of telomerase inhibitor or Bcl-2 inhibitor.
36. Likewise, the scope of hematological disorders is extremely broad, complex in pathology and embraces hundreds of thousands of possible disorders, including cancer(s):
“a hematological cancer selected from: acute myeloid leukemia; essential thrombocythemia; polycythemia vera; primary myelofibrosis; systemic mastocytosis; chronic myeloid leukemia; chronic neutrophilic leukemia; chronic eosinophilic leukemia; refractory anemia with ringed sideroblasts; refractory cytopenia with multilineage dysplasia; refractory anemia with excess blasts; type 1; refractory anemia with excess blasts; type 2; myelodysplastic syndrome (MDS) with isolated del (5q); MDS unclassifiable; chronic myelomonocytic leukemia (CML); atypical chronic myeloid leukemia; juvenile myelomonocytic leukemia; myeloproliferative/myelodysplastic syndromes-unclassifiable; B lymphoblastic leukemia/lymphoma; T lymphoblastic leukemia/lymphoma; diffuse large B-cell lymphoma; primary central nervous system lymphoma; primary mediastinal B-cell lymphoma; Burkitt lymphoma/leukemia; follicular lymphoma; chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma; B-cell prolymphocytic leukemia; lymphoplasmacytic lymphoma/ Waldenstrom macroglobulinemia; Mantle cell lymphoma; marginal zone lymphomas; post-transplant lymphoproliferative disorders; HIV-associated lymphomas; primary effusion lymphoma; intravascular large B-cell lymphoma; primary cutaneous primary cutaneous B-cell lymphoma; hairy cell leukemia; monoclonal gammopathy of unknown significance; smoldering multiple myeloma; and solitary plasmacytomas (solitary bone and extramedullary).”
(Specification, pages 4-5).
37. As such, the claim is extremely broad with respect to the disclosure. The second inquiry is discussed in detail below.
38. The amount of experimentation necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to a method of treating any/ all hematological disorder(s), inducing apoptosis in any hematological cancer cell, comprising administering any telomerase inhibiting compound and any Bcl-2 inhibiting compound to a subject in need thereof, wherein the telomerase inhibitor is administered at a dose of about 0.5 mg/kg to 30 mg/kg, and the Bcl-2 inhibitor is administered at a dose of about 50 to 400 mg.
39. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of the scope of the claims with respect to the disclosure since the scope of said telomerase inhibitors and Bcl-2 inhibitors encompass hundreds of thousands of possible combinations, whereas the instant Specification discloses the administration of just one compound species of each type exerting the disclosed activity. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan could not reasonably predict which of the hundreds of thousands of compounds encompassed by the claims would exert the alleged activity based on the limited disclosure. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. As evidenced by Cleveland Clinic, above, the scope of the recited hematological disorders embraces significant variance and unpredictability in human diseases/ disorders/ cancers etc, and current treatment present many challenges. Thus, it is highly unpredictable whether any compounds within the genus of telomerase inhibitors and the genus of Bcl-2 inhibitors encompassed by the claims based on the instant disclosure would, in fact, be usable. Whether the other compounds encompassed by the claims would be usable is even less predictable. As such, the only way to ascertain which of the thousands, and potentially hundreds of thousands of claimed compounds presently encompassed by the claims are usable based on the limited disclosure would require undue experimentation. That is, the only way one skilled in the art is enabled to use the entire scope of the claim based on the instant disclosure entails undue experimentation.
To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
New Claim Rejections - 35 USC § 103
40. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
41. Claims 1, 3, 4, 7, 8, 10-13, 15, 18 and 42-46 are rejected under 25 U.S.C. 103 as being unpatentable over Kuo et al., Cell Stem Cell (2014), as evidenced by PubChem (https://pubchem.ncbi.nlm.nih.gov/compound/Imetelstat-sodium 2014), in view of Konapleva et al., Blood (2014), and further in view of Cantilena et al., (https://ashpublications.org/blood/article/126/23/1267/104593/Activity-of-the-Telomerase-Inhibitor-GRN163L 2015).
This rejection is newly applied as a result of Applicant’s amendatory changes to claims 1 and 18.
Claim 1, as amended, is directed to a method of treating a hematological cancer (more specifically, acute myeloid leukemia (AML) (claim 3)) in a subject in need thereof, comprising administering a telomerase inhibitor (more specifically, imetelstat or a pharmaceutically acceptable salt thereof (claim 4)) and a Bcl-2 inhibitor (more specifically, ABT-199 (claim 7)) to said subject,
wherein the telomerase inhibitor is administered at a dose of about 0.5 mg/kg to 30 mg/kg; and
the Bcl-2 inhibitor is administered at a dose of about 50-400 mg, daily (claim 8), more specifically 400 mg daily (claim 42); or 100 mg daily (claim 43).
Claim 18, as amended, is directed to a method of treating acute myeloid leukemia in a subject in need thereof, comprising administering imetelstat or a pharmaceutically acceptable salt thereof and ABT-199 to said subject having AML,
wherein the imetelstat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg/kg to 30 mg/kg; and
and the ABT-199 or a pharmaceutically acceptable salt thereof is administered at a dose of about 50-400 mg, daily, (claim 44); more specifically 400 mg daily (claim 45); or 100 mg/daily (claim 46).
Claim 10 is directed to a method of inducing apoptosis in a hematological cell (more specifically, an AML cell (claim 15)), comprising contacting said cell with a therapeutically effective amount of a telomerase inhibitor (more specifically, imetelstat or imetelstat sodium (claims 11 or 12)), and contacting said cell with a therapeutically effective amount of a Bcl-2 inhibitor (more specifically, ABT-199 (claim 13)).
42. Kuo et al. disclose the activity of the telomerase inhibitor imetelstat against acute myeloid leukemia (AML) cells in patient samples, i.e.:
“imetelstat (GRN163L), a pharmacological telomerase inhibitor, showed significant activity against primary human AML cells… Administration of imetelstat prevented AML development in primary human xenografts and leukemia progression remained significantly delayed for weeks after suspension of treatment. Importantly, addition of imetelstat to chemotherapy reduced or delayed leukemia relapse compared to chemotherapy alone,” [emphasis added]
(Page 2, third paragraph, lines 12-16). And, it is clear as evidenced by Pubchem that GRN163L is the sodium salt of imetelstat, (see under “Synonyms”).
43. Kuo et al. teach that telomerase deficiency in AML cells resulting from the administration of the telomerase inhibitor GRN163L is characterized by increased apoptosis, which meets the limitation of claim 10 (Page 2, second paragraph). Based on the teaching of Kuo et al, one skilled in the art before the effective filing date of the claimed invention would have been motivated to administer the known telomerase inhibitor imetelstat sodium to a subject having AML, and would have had a reasonable expectation of success that said administration would induce apoptosis of AML cells. Thus it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to administer imetelstat sodium to a subject having AML, resulting in the successful treatment of AML in said subject in need thereof.
44. As such, Kuo et al. suggest treating AML in a subject by administering imetelstat sodium to a subject in need thereof, but do not teach the but do not teach the administration of ABT-199.
45. Yet, Konopleva et al. teach the administration of the orally bioavailable BCL-2 inhibitor ABT-199 to patients diagnosed with high-risk AML, wherein ABT-199 demonstrates “considerable clinical activity” (Page 1, Introduction and Page 3, Conclusions). Konopleva et al. teach daily dosage amounts that are within the range of 20-800 mg ABT-199 required by claims 8 and 42-46:
“pts received 20 mg ABT-199 on Week (Wk) 1 Day 1, with daily escalation to a final target dose of 800 mg on Day 6 and daily thereafter,” (Page 2, first paragraph).
A daily dose range of from 2o mg/day -800 mg/day fully embraces the daily dose of about 50-400 mg required by claim 8, the daily dose of 400 mg required by claims 42 and 45, the dose of 100 mg daily required by claims 43 and 46, the daily dose of about 50-400 mg required by claim 44. And, dose regimen optimization is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize given the guidance of the prior art. The determination of known effective amounts of known active agents to be administered to treat the same disease (in this case, AML) is considered well in the competence level of an ordinary skilled artisan in pharmaceutical science, involving merely routine skill in the art. It has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. As Konopleva et al. teach a dosage regimen of ABT-199 that is used to treat AML, and how to gradually escaleate that dosage based on side effects/adverse events, the dosage amount is considered a result-effective variable. Thus, it would also have been obvious to have chosen a dosage from among those dose amounts known to be effective in methods of treating AML.
46. Kuo et al. do not teach the dosage amount of imetelstat or a pharmaceutically acceptable salt thereof.
47. Yet, Cantilena et al. teach the administration of imetelstat to treat an AML cell line at dosages of 1.25 M, 2.5 M, 5 M, 10 M, 20 M and 40 M, which are equivalent to mg dosages of 5.76 mg, 11.53 mg, 23.0 mg, 46.1 mg, 92.2 mg, and 184.4 mg, when converted to mg (using the molecular weight of imetelstat of 4610 g/moL, as evidenced by PubChem), which overlap a range of imetelstat of about 0.5 - 9.4 mg/kg (assuming a 62 kg human) and is within the range required by claim 1. And, MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). And, "A prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). >See also In re Harris, 409 F.3d 1339, 74 USPQ2d 1951 (Fed. Cir. 2005).
48. As such, one skilled in the art before the effective filing date of the claimed invention would have been motivated to treat AML in a subject in need thereof by administering the combination of imetelstat or a pharmaceutically acceptable salt thereof in an amount of about 0.5 - 9.4 mg/kg, and ABT-199 in an amount of from 50-400 mg to treat AML to said subject, with a reasonable expectation of success.
49. It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to administer said combination because each of imetelstat sodium and ABT-199 has previously demonstrated apoptosis against AML cells in vitro and activity against AML in vivo. And, the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law, please see In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings). Furthermore, MPEP 2144 teaches that the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.
50. In the instant case, two known compounds which individually demonstrate activity against AML could be combined in order to achieve an additive effect for treating AML in a subject, or to induce apoptosis in AML cells in vitro, with the expected result of successfully treating/ inhibiting the progression of AML.
51. Please refer to MPEP 2144.06 “I. COMBINING EQUIVALENTS KNOWN FOR THE SAME PURPOSE” wherein Kerkhoven is specifically referenced:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
52. As stated by the Court in KSR International Co., v. Teleflex Inc., 127 US 1727 (2007), “when a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious” (quoting Sakraida v. AG Pro, Inc., 425 US 273 (1976); see also: Merck v. Biocraft (874 F.2d 804, 807 (Fed. Cir. 1989), indicating that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands; Sundance, Inc. v. DeMonte Fabricated, Ltd., 550 F.3d 1356 (Fed. Cir. 2008): a claimed invention is obvious is it is a combination of known prior art elements that would reasonably have been expected to maintain their respective properties or functions after they had been combined; Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327 (1945): indicating that “[r]eading a list and selecting a known component to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle”; Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356 (Fed. Cir. 2012): finding a “strong case of obviousness based on the prior art references of record [wherein the claim] recites a combination of elements that were all known in the prior art, and all that was required to obtain that combination was to substitute one well-known…agent for another”).
53. In the instant case, (1) each prior art element, imetelstat and ABT-199, performs the function specified in the claim, (i.e., treatment of AML or apoptosis of an AML cancer cell); (2) the claimed components (i.e., imetelstat and ABT-199) and their function(s) were known in the art; (3) a person of ordinary skill in the art would have recognized that combining the elements would achieve a greater than additive effect in the treatment of AML; and (4) the results of the combination would have been predictable (i.e., successful treatment of AML in a subject in need thereof).
As such, claims 1, 3, 4, 7, 8, 10-13, 15, 18 and 42-46 are prima facie obvious.
Claim 5, as amended, is drawn to claim 4, and limits wherein the imetelstat or a pharmaceutically acceptable salt thereof (more specifically, imetelstat sodium (claim 6)) is administered for 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosage cycles, each cycle comprising:
(a) intravenous administration of about 7 - 10 mg/kg imetelstat or a pharmaceutically acceptable salt thereof once every four weeks;
(b) intravenous administration of about 2.5 - 10 mg/kg imetelstat or a pharmaceutically acceptable salt thereof once every three weeks; or
(c) intravenous administration of about 0.5 - 9.4 mg/kg imetelstat or a pharmaceutically acceptable salt thereof once every four weeks.
Claim 19, as amended, is drawn to claim 18, and limits wherein the imetelstat or a pharmaceutically acceptable salt thereof is administered for 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosage cycles, each cycle comprising:
(a) intravenous administration of about 7 - 10 mg/kg imetelstat or a pharmaceutically acceptable salt thereof once every four weeks;
(b) intravenous administration of about 2.5 - 10 mg/kg imetelstat or a pharmaceutically acceptable salt thereof once every three weeks; or
(c) intravenous administration of about 0.5 - 9.4 mg/kg imetelstat or a pharmaceutically acceptable salt thereof once every four weeks.
54. Cantilena et al. additionally teach the administration of imetelstat to treat an AML cell line at dosages of 1.25 M, 2.5 M, 5 M, 10 M, 20 M and 40 M, which are equivalent to mg dosages of 5.76 mg, 11.53 mg, 23.0 mg, 46.1 mg, 92.2 mg, and 184.4 mg, when converted to mg (using the molecular weight of imetelstat of 4610 g/moL, as evidenced by PubChem), which overlaps the range of imetelstat of about 0.5 - 9.4 mg/kg required by step (c) of claim 5 and claim 19 (assuming a 62 kg human). MPEP 2144.05 states: In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). And, "A prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). >See also In re Harris, 409 F.3d 1339, 74 USPQ2d 1951 (Fed. Cir. 2005).
55. Regarding the dosage amount and frequency of administration of the imetelstat recited in steps (a) and (b) of claims 5 and 19, Cantilena et al. do not disclose the exact claimed weight values, but do overlap: in such instances even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). Normally it is to be expected that a change in temperature, or in concentration, or both, would be a patentable modification. Under some circumstances, however, changes such as these may impart patentability to a process if the particular changes claimed produce a new and unexpected result which result is different in kind and not merely in degree from the results of the prior art. Such ranges are termed "critical" ranges, and the Applicant has the burden of proving such criticality. However, even if Applicant's modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art. More particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
56. As such, one skilled in the art before the effective filing date of the claimed invention would have been motivated to optimize administration of imetelstat sodium by employing at least one dosage cycle of intravenous administration of about 0.5 - 9.4 mg/kg imetelstat sodium once every four weeks. It would have been obvious to one of skill in the art before the effective filing date of the claimed invention to employ at least one dosage cycle of intravenous administration of about 0.5 - 9.4 mg/kg imetelstat sodium once every four weeks, with a reasonable expectation of success.
As such, claims 5, 6 and 19 are prima facie obvious.
Claim 9 is drawn to the method of claim 7, and limits where ABT-199 is administered one day before, one day after, or the same day as the administration of the telomerase inhibitor.
57. Kuo et al. in view of Konopleva et al. and in view of Cantilena et al. do not suggest order of administration. However, optimization of parameters (in this case, administration) is a routine practice that would be obvious for a person of ordinary skill in the art to employ. And, discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art (in this case, the variable is order of administration). See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
58. As such, one of skill in the art before the effective filing date of the claimed invention would have been motivated to optimize the order of administration of ABT-199 relative to the administration of imetelstat, i.e., one day before, one day after, or the same day as the administration of imetelstat, thus resulting in the practice of claim 9. It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to optimize parameters such as the order of administration, for treating AML in a patient in need thereof, with a reasonable expectation of success.
Response to Arguments
59. Applicant traverses the previous obviousness rejection of claims 1, 3, 4, 7-13, 15, 18 and 42-46 over Kuo et al. in view of Konopleva et al., and of claims 5, 6 and 19 over Kuo et al. in view of Konopleva et al. further in view of Cantilena et al., and argues the following points:
(i) Applicant argues that Kuo is solely cited for allegedly teaching the activity of the telomerase inhibitor imetelstat against acute myeloid leukemia (AML) cells, but fails to teach or suggest the administration of ABT-199 in combination with a telomerase inhibitor. Applicant alleges that there is no teaching in Kuo regarding a therapeutically effective amount of the telomerase inhibitor for the treatment of AML.
Applicant argues that Cantilena is cited for allegedly teaching the administration of imetelstat to treat an AML cell line at dosages of 1.25 mM, 2.5 mM, 5 mM, 10 mM, 20 mM and 40 mM, which are equivalent to mg dosages of 5.76 mg, 11.53 mg, 23.0 mg, 46.1 mg, 92.2 mg, and 184.4 mg, when converted to mg (using the molecular weight of imetelstat of 4610 g/moL, as evidenced by PubChem), which overlaps the range of imetelstat of about 0.5 - 9.4 mg/kg. Applicant argues that Cantilena fails to teach or suggest the administration of ABT-199 in combination with the telomerase inhibitor.
Applicant argues that Konopleva is related to ABT-199 monotherapy in patients with high risk relapsed/refractory AML and those unfit for chemotherapy. Applicant alleges that there is no teaching or suggestion in Konopleva that ABT-199 can be used in combination with other drugs, such as telomerase inhibitor, for combination therapy.
60. Applicant's arguments have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, the prior art elements imetelstat and ABT-199 and their respective dose amounts are each previously taught for the treatment of AML or apoptosis of an AML cancer cell, and one of ordinary skill in the art would have recognized that combining said elements would achieve a greater than additive effect in the treatment of AML, with a reasonable expectation of success.
(ii) Applicant contends that regarding dosage of ABT-199, Konopleva suggests a dose escalation to a final target dose of 800 mg on day 6, and therefore “one of ordinary skill would not be motivated to select Bcl-2 inhibitor at a dose of about 50 to 400 mg in combination with telomerase inhibitor at a dose of about 0.5 mg/kg to 30 mg/kg for combination therapy.
61. Applicant's arguments have been fully considered but they are not persuasive. While Konopleva does teach a final target dose of 800 mg/day, Konopleva also teaches an initial dose of 20 mg/day. The range of from 2o mg/day -800 mg/day fully embraces the dose of about 50-400 mg required by claim 1. And, discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art (in this case, dose amount). See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980), thus resulting in the optimization of the dose of ABT-199, with a reasonable expectation of success.
It is noted that instant Claim 1 fails to limit or define the frequency of administration (i.e., once per day, twice per day, etc) such that claim 1 presently embraces administering the Bcl-2 inhibitor in any dose amount greater than 50 mg per day.
(iii) Applicant argues that the claimed invention provides unexpected results that represent significantly more than the predictable use of prior art elements according to their established functions. Applicant argues that in the Specification at Example 1, the telomerase inhibitor imetelstat was tested in combination with ABT-199, at various concentrations of each, against the AML tumor cell line KG-1. In Figure 1B, a greater than additive effect of cell death is observed when imetelstat sodium is administered at a dose of 50 mM in combination with ABT-199 at a dose of either 100 nm or 500 nM (Specification Figure 1B at paragraph [0121]). Likewise, the results of various concentrations of the telomerase inhibitor imetelstat were tested in combination with various concentrations of ABT-199, against the AML tumor cell line MOLM-13, as shown in Figure 5B. Applicant argues that a greater than additive effect of cell death is observed when 50 mM imetelstat sodium is administered in combination with either 100 nM or 500 nM ABT-199 (Specification Figure 5B at paragraph [0124] and Figure 6B at paragraph [0125]). Applicant argues that in Example 3, the combination of imetelstat and ABT-199 exhibits dose-dependent synergistic effects on AML tumor cells in vitro; and in Example 4, an ex vivo study of AML patient PBMC samples showed that significantly reduced cell viability is observed following treatment with imetelstat in combination with ABT-199 as opposed to either treatment alone, (Specification at paragraph [0144]); and in Example 5, an in vivo disseminated mouse model of MOLM-13 AML demonstrating that the combination of 30 mg/kg imetelstat with 100 mg/kg ABT-199 demonstrated a synergistic effect (Figure 16 and Specification at paragraph [0150]).
62. Applicant's arguments have been fully considered but they are not persuasive. It is well settled that a showing of unexpected results is generally sufficient to overcome a prima facie case of obviousness. In re Albrecht, 514 F.2d 1389 (CCPA 1975). In the instant case, Applicant has demonstrated evidence that establishes greater than additive results in the treatment of AML tumor cell lines following the administration of the specific combination of imetelstat sodium and ABT-199 at certain concentrations in Examples 1-5 in the Specification and Figures 1B, 2B, 5B, and 6B. However, although the evidence establishes greater than expected results, Applicant is reminded that “the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support” (In re Clemens, 622 F.2d 1029 (CCPA 1980)). Thus, in In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003), factual evidence demonstrating a greater than expected result from the addition of 2% of an ingredient did not evidence unexpected results for the entire claimed range of about 1-3% of the ingredient. Rather, the nonobviousness of a broader range or genus can only be established by evidence based on unexpected results of a narrower range or genus when one of ordinary skill in the art would be able to determine a trend in the exemplified data allowing said artisan to reasonably extend the probative value thereof. In re Kollman, 595 F.2d 48 (CCPA 1979).
63. In the instant case, the claims are not drafted commensurate in scope with the greater than expected results referenced above by Applicant and demonstrated in Figures 1B, 2B, 5B, 6B and 16. Specifically, the claims presently embrace the treatment of any hematological cancer comprising administering any telomerase inhibitor in combination with any Bcl-2 inhibitor. It is recommended that the claims be drafted commensurate in scope with the greater than additive effects of the treatment of AML in a subject, i.e., comprising administering the combination of imetelstat sodium and ABT-199, at the critical concentration(s) for each, demonstrated in the Specification and in Figures 1B, 2B, 5B, 6B and 16, for example. Claims 1 and 18 have been amended to incorporate the dosage range of the telomerase inhibitor and the Bcl-2 inhibitor, however no claim recites the administration of the specific combination of imetelstat or a pharmaceutically acceptable salt thereof and ABT-199 or a pharmaceutically acceptable salt thereof in dosages that are commensurate with the greater than additive effects shown in the Specification.
64. Since the combined features upon which Applicant relies, i.e., the dose-dependent synergistic effects of the combination of imetelstat or a pharmaceutically acceptable salt thereof and ABT-199 on AML in a subject in need thereof are not recited in any of the rejected claim(s), the obviousness rejection is maintained.
Conclusion
65. In conclusion, claims 1, 3-13, 15-22, and 42-46 are pending in the application. Claims 16, 17 and 20-22 are presently withdrawn as directed to a non-elected invention. Claims 1, 3-13, 15, 18, 19 and 42-46 are rejected. No claim is presently allowable.
66. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached on Monday-Friday 8:30AM-5PM EST.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628