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 .
Claim Status
The claim set and Applicant’s remarks filed August 01, 2025 have been entered. Claims 3-4 are cancelled. Claims 11-21 are new. Thus, claims 1-2 and 5-21 as amended are examined on the merits herein.
Withdrawn Objections and Rejections
With respect to the objections and/or rejections mailed in the non-final office action on May 01, 2025:
(I) The objection of claim 3 is withdrawn in view of Applicant canceling claim 3 as discussed above.
(II) The rejection of claims 1, 4, 6-7 and 10 under 35 U.S.C. 102(a)(1);
(III) The rejection of claims 1, 4, 6-7 and 9-10 under 35 U.S.C. 103;
(IV) The rejection of claims 1, 4, 6-8 and 10 under 35 U.S.C. 103;
(V) The rejection of claims 1, 3-4, 6-7 and 10 under 35 U.S.C. 103;
(VI) The rejection of claims 1, 3-7 and 10 under 35 U.S.C. 103 and
(VII) The rejection of claims 1-2, 4, 6-7 and 10 under 35 U.S.C. 103 are withdrawn in view of Applicant amending claim 1 wherein the oral ulcer is caused by chemotherapy and wherein the medicament comprises one or more active ingredients as recited in claim 1, lines 4-9.
Response to Arguments
The rejection of claims 1-2 and 5-10 under 35 U.S.C. 103 is maintained.
Applicant argues:
The 103 rejections do not contain a medicament containing two or more active ingredients as recited in claim 1, see Applicant’s remarks, pg. 7/8, paragraph 2.
However, the Examiner respectfully notes the combination of Liu-1 and Jun In teach a method of administering anemoside B4 as taught by Liu-1 and poly I:C as taught by Jun In in treating an EV71 viral infection which causes hand-foot-mouth disease (HFMD), which manifests as oral mucosal ulcerative herpes as discussed in further detail in the new 103 rejections discussed below.
Moreover, the Examiner respectfully notes the combination of Verma and Zhang as evidenced by Xu teach a method of administering rifampicin as taught by Verma and anemoside B4 as taught by Zhang as evidenced by Xu in treating oral tuberculosis, which manifests as intraoral non-healing ulcers as discussed in further detail in the new 103 rejections discussed below.
Thus, Applicant’s argument has been fully considered but is not found persuasive.
Claim Objections
Claims 1 and 6 are objected to because of the following informalities:
Claim 1, line 1, recites “treating oral ulcer” which is clearly missing the article “an” immediately before the recitation of “oral”. Thus, to promote clarity the Examiner suggests inserting the word “an” immediately before the word “oral” as discussed above.
Claim 6, line 1, recites “medicament is s an” which recites a superfluous letter “s” immediately before the word “an”. Thus, to promote clarity the Examiner suggests deleting the word “s” as discussed above.
Appropriate correction is required.
New Claim Rejections
The following are new grounds or modified rejections necessitated by Applicant's amendment, filed on August 01, 2025, where the limitations in pending claims 1-2 and 5-10 as amended now have been changed and claims 11-21 have been newly added. Therefore, rejections from the previous Office Action, dated May 01, 2025, have been modified and are listed below.
35 USC § 112
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 5 and 11-21 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.
Claim 5, lines 1-3 recite the phrase “wherein the medicament comprises further comprises a second active ingredient of rifampicin”. The Examiner respectfully notes the phrase “comprises further comprises” is grammatically incorrect and thus the Examiner reasonably interprets the phrase “comprises further comprises” to mean “further comprises”.
The Examiner also respectfully notes claims 11-21 recite the phrase “wherein the medicament further comprises” when referring to the specific second active ingredient recited within each of these claims that are within the medicament as recited in claim 1.
Although, the Examiner respectfully notes claims 5 and 11-21 depend from claim 1, wherein the medicament already comprises anemoside B4 as a first active ingredient and one or more active ingredients selected from the group consisting of and including each second active ingredient as recited in claims 5 and 11-21 respectively.
Therefore, the recitation of “wherein the medicament further comprises” in each of claims 5 and 11-21 as discussed above when referring to the one or more active ingredients within the medicament of claim 1 is confusing, unclear and thus indefinite as to what is being claimed within claims 5 and 11-21 respectively.
For example with respect to claim 5, does claim 1 include rifampicin as the one or more active ingredients; or is it a separate additional active ingredient that is further added as recited by the phrase “the medicament further comprises” within claim 5 as discussed above. The Examiner also respectfully notes these interpretations apply to claims 11-21 as well.
As a result, there are two reasonable interpretations for claims 5 and 11-21 which will be illustrated using claim 5 below:
(i) based on the phrase “one or more active ingredients” within lines 4-5 of claim 1, claim 5 can be interpreted to mean “wherein the one or more active ingredients includes rifampicin”; or
(ii) based on the phrase “the medicament further comprises a second active ingredient of rifampicin”, the rifampicin is not required within the “one or more active ingredients” as recited in claim 1 and thus is separately added as an additional active ingredient of the medicament as recited within claim 5.
In the interest of compact prosecution the Examiner will interpret each of claims 5 and 11-21 to mean wherein the one or more active ingredients includes the structure(s) recited in claims 5 and 11-21 respectively.
35 USC § 103
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.
(I) Claims 1, 6-8 and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (hereafter referred to as "Liu-1", Published 10 August 2017, WO-2017133468-A1, Using the NPL English Machine Translation, PTO-892 mailed 05/01/2025) in view of Naidu et al. (Published September-October 2004, Neoplasia, Vol. 6, Issue 5, pp. 423-431, PTO-892 mailed 05/01/2025) and Ju In et al. (Published 24 May 2017, PLOS One, Vol. 12, Issue 5, pp. 1-11, PTO-892).
Regarding claims 1, 6-8 and 10-11, Liu-1 teaches a Pulsatilla saponin compound and the use thereof as a medicament for the treatment of an EV71 virus infection or a disease caused by an EV virus infection, for example hand-foot-and-mouth disease (HFMD), see pg. 4, technical filed, paragraph 1.
Liu-1 teaches the main manifestations of HFMD include fever, oral mucosal ulcerative herpes (e.g. the oral ulcer, required in claim 1) and blister-like rash at the extremities, see pg. 4, background technique, paragraph 1. Liu-1 teaches treating an EV71 infection or disease caused by an EV71 infection, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), see pg. 7, paragraph 2.
Liu-1 teaches the compound is selected from the compounds in Table 1, wherein the first compound in Table 1 is Pulsatilla saponin B4 (also known as anemoside B4), see WO-2017133468-A1, pg. 5, first structure recited within the table. The Examiner notes the first compound recited in Table 1 of Liu-1 corresponds to the structure recited within Applicant’s specification as structural formula 1 which the Applicant discloses is anemoside B4 (see pg. 2, lines 10-15, structural formula 1).
Liu-1 teaches evaluation of the therapeutic effect of Pulsatilla saponin B4 on mice infected with EV71 virus, see pg. 9, section 3.3; wherein the results indicate that Pulsatilla saponin B4 can significantly improve the survival rate of mice infected with EV71 virus and can be used for treating EV71 virus infection and diseases caused by EV71 virus infection, see pg. 10, paragraph 2, lines 7-8.
Liu-1 teaches the compounds can be administered via oral, parenteral, rectal, pulmonary or topical administration, see pg. 8, paragraph 4, lines 1-2. Liu-1 teaches liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, elixirs, capsules, tablets, pills, powders and granules (e.g. an oral preparation required in claim 6), see pg. 8, paragraph 4, lines 2-3. Liu-1 teaches the dosage form for parenteral administration may be an injection preparation (e.g. a non-oral preparation, required in claims 7-8), see lines 12-14.
Liu-1 teaches the subject is a mammal, such as a human, see pg. 8, paragraph 3.
With respect to the limitation of treating an oral ulcer required in claim 1; the Examiner reasonably interprets this as a physical consequence of administering anemoside B4. Since Liu-1 teaches administering anemoside B4 for treating HFMD that manifests as oral mucosal ulcerative herpes, the physical consequence is met.
Although, Liu-1 does not teach (a) the oral ulcer is caused by chemotherapy, required in claim 1, line 3; and (b) wherein the medicament comprises poly I:C, required in claim 11.
However, in the same field of endeavor of oral ulcerations, with respect to limitation (a), Naidu teaches chemotherapy induced oral mucositis complicating the treatment of cancer, see pg. 423, title. Naidu teaches within 1 week of therapy epithelial breakdown ultimately results in the ulcerative phase, see pg. 424, right column, phase III, lines 2-3.
Naidu teaches oral complications that arise with chemotherapy include mucositis (stomatitis) and bacterial or viral infection, see pg. 423, right column, introduction, paragraph 1, lines 9-11.
Naidu teaches the oral mucosa of cancer patients is colonized by a variety of potentially pathogenic microorganisms; wherein viruses represent the most common pathogens aggravating oral mucositis in the course of antineoplastic therapy, see pg. 429, left column, antimicrobial/antifungal/antiviral agents, paragraph 1.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the invention’s effective filing date to have included the oral ulcer is caused by chemotherapy into the method of Liu, as Naidu teaches chemotherapy induces oral mucositis, wherein ulcerations occur after 1 week of treatment; and teaches oral complications include viral infection which arises from chemotherapy treatment which represent the most common pathogens aggravating oral mucositis in the course of antineoplastic therapy as discussed above.
In addition, Liu-1 teaches the EV71 virus causing HFMD manifests as oral mucosal ulcerative herpes treated with anemoside B4 as discussed above. Thus, one of ordinary skill in the art would have been motivated to include the oral ulcer is caused by chemotherapy into the method of Liu-1 above because anemoside B4 is already employed for the same purpose of treating oral mucosal ulcerations caused by an EV71 viral infection as taught by Liu-1 above; and further in view of Naidu which teaches viral infections are a known and most common oral complication which arises from chemotherapy treatment for cancer patients as discussed above.
Moreover, one of ordinary skill in the art would have had a reasonable expectation of success to have included the oral ulcer is caused by chemotherapy, as Naidu teaches viral infections occur as oral complications caused by chemotherapy treatment and represent the most common pathogen that aggravates oral mucositis during antineoplastic treatment as taught by Naidu above.
Furthermore, with respect to limitation (b), Ju In teaches adjuvants for the EV71 vaccine include polyinosinic-polycytidylic acid (e.g. poly I:C, required in claim 11) and was administered separately with the FI-EV71 vaccine to mice via the intramuscular route, see pg. 1, abstract.
Ju In teaches poly I:C is a synthetic analog of double-stranded RNA which is used to mimic viral infection, see pg. 2, introduction, paragraph 3.
Ju In teaches formalin-inactivated EV71 vaccine (FI-EV71) derived from a patient who showed clinical signs of HFMD and belonged to the C4 subgenogroup was developed, and the efficacy of FI-EV71 with various adjuvants was evaluated in mice, see pg. 2, introduction, paragraph 4.
Ju In teaches the group administered FI-EV71 formulated with poly I:C adjuvant induced higher antibody titers than other groups vaccinated with a single adjuvant (alum or MPLA). Thus, the addition of poly I:C was critical for boosting neutralization antibodies against EV71, see pg. 7, paragraph 2.
It would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have included limitations (a)-(b) into the method as taught by Liu-1 above as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to make the addition of limitation (a) as discussed above in order to treat the EV71 viral infection which causes oral mucosal ulcerations in the patient of Liu-1, as Naidu teaches viral infections are a known and most common oral complication of chemotherapy treatment as discussed above; and to have included limitation (b) as Jun In teaches poly I:C as a vaccine adjuvant for EV71 which induced higher antibody titers than other groups vaccinated as discussed above; and wherein the Examiner notes EV71 is the identical viral strain as taught by Liu-1 above.
One of ordinary skill in the art would have had a reasonable expectation of success to have included limitations (a)-(b) into the method of Liu-1; as Naidu teaches viral infection represents the most common pathogen aggravating oral mucositis in the course of antineoplastic therapy; Liu-1 teaches the use of anemoside B4 in treating EV71 viral infection or a disease caused by EV71 viral infection manifesting as oral mucosal ulcerative herpes; and Jun In teaches the use of poly I:C as an adjuvant critical for boosting neutralization antibodies against EV71 as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(II) Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Liu-1 (Published 10 August 2017, WO-2017133468-A1, PTO-892 mailed 05/01/2025, Using the NPL English Machine Translation) as applied to claims 1, 6-8 and 10-11 above, and further in view of Liu (hereafter referred to as "Liu-2", Published 12 June 2018, CN-108143710-A, IDS filed 09/06/2022, Using the NPL English Machine Translation).
Liu-1addresses claims 1, 6-8 and 10-11 as written above. Although, Liu-1 does not teach the rectal preparation as rectal suppositories or rectal gels required in claim 9.
However, in the same field of endeavor of rectal administration of anemoside B4, Liu-2 teaches a mucous membrane rectum drug-delivery preparation of anemoside B4 and preparation method thereof, see pg. 1, title.
Liu-2 teaches the mucous membrane is selected from one or both of a rectum gelling agent and rectal suppositories, see pg. 1, abstract, lines 2-4.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have chosen another route of administration of the oral preparation of anemoside B4 taught by Liu-1 above by choosing the rectal gels or rectal suppositories containing anemoside B4 taught by Liu-2 above as within the scope of the artisan as a simple substitution of one known element for another to obtain predictable results. One of ordinary skill in the art would have been motivated to formulate the composition of Liu-1 as a rectal gelling agent or rectal suppositories as taught by Liu-2 in order to administer the composition of Liu-1 via rectal administration as taught by Liu-1 above. One of ordinary skill in the art would have had a reasonable expectation of success to have chosen a different route of administration as discussed above, as Liu-1 teaches rectal administration of anemoside B4 as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(III) Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Liu-1 (Published 10 August 2017, WO-2017133468-A1, PTO-892 mailed 05/01/2025, Using the NPL English Machine Translation) as applied to claims 1, 6-8 and 10-11 above, and further in view of Dias et al. (Published Jan-Feb 2012, Annals of Tropical Medicine and Public Health, Vol. 5, Issue 1, pp. 40-41, PTO-892 mailed 05/01/2025).
Liu-1addresses claims 1, 6-8 and 10-11 as written above. Although, Liu-1 does not teach wherein the oral ulcer is a recurrent oral ulcer, required in claim 2.
However, in the same field of endeavor of hand-foot-and-mouth disease (HFMD), Dias teaches the recurrence of hand-foot-and-mouth disease in a child, see pg. 40, title.
Dias teaches a 9-year-old child presented with a history of oral ulcers on the lips and buccal mucosa, and the diagnosis of HFMD was made on the clinical grounds because of the pathognomic clinical presentation, see pg. 40, left column, case report, paragraph 1.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated wherein the oral ulcer is a recurrent oral ulcer as taught by Dias above into the method of Liu-1 as discussed above as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to treat the EV71 infection which causes HFMD as taught by Liu-1 above. One of ordinary skill in the art would have had a reasonable expectation of success to have included wherein the oral ulcer is a recurrent oral ulcer as taught by Dias above into the method of Liu-1 above, as Dias teaches the recurrence of hand-foot-and-mouth disease in a child and wherein the child presented with a history oral ulcers on the lips and buccal mucosa as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(IV) Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Liu-1 (Published 10 August 2017, WO-2017133468-A1, PTO-892 mailed 05/01/2025, Using the NPL English Machine Translation) as applied to claims 1, 6-8 and 10-11 above, and further in view of Peng et al. (Published 30 April 2016, Cellular and Molecular Biology, Vol. 62, Issue 4, pp. 35-41, PTO-892).
Liu-1 addresses claims 1, 6-8 and 10-11 as written above. Although, Liu-1 does not teach the medicament comprising granulocyte-macrophage colony stimulating factor (GM-CSF), required in claim 12.
However, in the same field of endeavor of hand-foot-mouth disease (HFMD), Peng teaches a novel EV71 DNA vaccine with plasmid VP1 DNA combined with GM-CSF DNA (e.g. GM-CSF, required in claim 12) was investigated, see pg. 38, right column, discussion, paragraph 1.
Peng teaches the mice which received pcDNA-GM-CSF adjuvant generated higher IgG antibodies than those in mice injected with the antigen-encoding plasmid alone, see pg. 39, right column, paragraph 3.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated the GM-CSF as taught by Peng above into the method of Liu-1 as discussed above as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to treat the EV71 infection which causes HFMD as taught by Liu-1 above by using the pcDNA-GM-CSF of Peng as an adjuvant for generating higher IgG antibodies as taught by Peng above. One of ordinary skill in the art would have had a reasonable expectation of success to have included the GM-CSF as taught by Peng above into the method of Liu-1 as discussed above; as Peng teaches the pcDNA-GM-CSF adjuvant generated higher IgG antibodies within subjects of the same patient population (e.g. subjects having an EV71 viral infection causing HFMD) as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(V) Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Liu-1 (Published 10 August 2017, WO-2017133468-A1, PTO-892 mailed 05/01/2025, Using the NPL English Machine Translation) as applied to claims 1, 6-8 and 10-11 above, and further in view of Girdler et al. (Published October 1995, American Journal of Clinical Oncology, Vol. 18, Issue 5, pp. 403-406, PTO-892).
Liu-1 addresses claims 1, 6-8 and 10-11 as written above. Although, Liu-1 does not teach the medicament comprising recombinant human epidermal growth factor (rh EGF), required in claim 13.
However, in the same field of endeavor of ameliorating the effects of chemotherapy, Girdler teaches the effect of epidermal growth factor (EGF) mouthwash on cytotoxic-induced oral ulceration, see pg. 1, title.
Girdler teaches there was a small delay in the onset and severity of recurrent ulceration between the experimental and placebo group and it was concluded that EGF mouthwash may have the potential to protect the oral epithelium from cytotoxic damage. See pp. 1-2, abstract.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated epidermal growth factor as taught by Girdler above into the method as taught by Liu-1 above as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to incorporate the epidermal growth factor as taught by Girdler above into the method of Liu-1 above, as Girdler teaches EGF provides a small delay in the onset and severity of recurrent ulceration. One of ordinary skill in the art would have had a reasonably expectation of success of including EGF into the method of Liu-1 above; as Liu-1and Girdler are drawn to oral ulcerations; Liu-1 teaches liquid dosage forms of the composition for oral administration which exemplifies solutions; and Girdler exemplifies a mouthwash comprising EGF as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(VI) Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Liu-1 (Published 10 August 2017, WO-2017133468-A1, PTO-892 mailed 05/01/2025, Using the NPL English Machine Translation) as applied to claims 1, 6-8 and 10-11 above, and further in view of Doerr et al. (Published 01 November 2001, International Journal of Radiation Oncology, Biology, Physics, Vol. 51, Issue 3, pp. 129-130, PTO-892).
Liu-1 addresses claims 1, 6-8 and 10-11 as written above. Although, Liu-1 does not teach the medicament comprises recombinant human keratinocyte growth factor (rh-KGF), required in claim 14.
However, in the same field of endeavor of ameliorating the effects of chemotherapy, Doerr teaches amelioration of acute radiochemotherapy effects in mouse oral mucosa by keratinocyte growth factor (rhKGF), see pg. 129, paragraph #231, title.
Doerr teaches mucosal ulceration was analyzed as the clinically relevant endpoint; where radiochemotherapy studies applied single injections of cisDDP, 5-FU or a combination of both 30 minutes before single dose irradiation, see pg. 130, paragraph 1.
Doerr teaches in a control experiment, the ED50, i.e. the dose after which ulcer induction is expected in 50% of the mice, when KGF was given before and after chemotherapy and irradiation, ED50s ranged around 19 Gy, see pg. 130, paragraph 4.
Doerr concludes their results indicate a marked increase in oral mucosal radiation tolerance by rhKGF, which is most pronounced if the growth factor is applied before single dose radiochemotherapy, see pg. 130, paragraph 5.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have included the rhKGF taught by Doerr above into the method as taught by Liu-1 above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to incorporate the rhKGF of Doerr into the composition of Liu-1, as Doerr teaches administration of KGF delayed oral ulceration during radiochemotherapy administration. One of ordinary skill in the art would have had a reasonable expectation of success to have included rhKGF as taught by Doerr above into the method of Liu-1 above, as Liu-1 and Doerr are both drawn to oral ulcerations; and as demonstrated by Doerr above within their chemotherapy studies the administration of rhKGF increased oral mucosal radiation tolerance during the administration of radiochemotherapy after which ulcer induction is expected in 50% of the mice as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(VII) Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Liu-1 (Published 10 August 2017, WO-2017133468-A1, PTO-892 mailed 05/01/2025, Using the NPL English Machine Translation) as applied to claims 1, 6-8 and 10-11 above, and further in view of Barbosa Ribeiro et al. (Published 23 October 2017, PLOS One, Vol. 12, Issue 10, pp. 1-17, PTO-892).
Liu-1 addresses claims 1, 6-8 and 10-11 as written above. Although, Liu-1 does not teach the medicament comprising dexamethasone, required in claim 16.
However, in the same field of endeavor of oral ulcerations, Barbosa Ribeiro teaches the protective effect of dexamethasone on 5-FU-induced oral mucositis in hamsters, see pg. 1, title.
Barbosa Ribeiro teaches the experimental groups included saline, MT, 5-FU, and DEX (0.25, 0.5, or 1 mg/kg); wherein DEX (0.5 or 1 mg/kg) reduced inflammation and ulceration of the oral mucosa of hamsters. Thus, DEX improved OM induced by 5-FU in hamsters. See pg. 1, abstract.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated dexamethasone as taught by Barbosa Ribeiro above into the method of Liu-1 as discussed above as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to include dexamethasone as taught by Barbosa Ribeiro in order to reduce inflammation and ulceration of the oral mucosa as taught by Barbosa Ribeiro above. One of ordinary skill in the art would have had a reasonable expectation of success to have included dexamethasone as taught by Barbosa Ribeiro above into the method of Liu-1 above; as Liu-1 and Barbosa Ribeiro are both drawn to oral ulcerations, wherein the administration of dexamethasone reduced inflammation and ulcerations of the oral mucosa within hamsters induced by chemotherapy as taught by Barbosa Ribeiro above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(VIII) Claims 19 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Liu-1 (Published 10 August 2017, WO-2017133468-A1, PTO-892 mailed 05/01/2025, Using the NPL English Machine Translation) as applied to claims 1, 6-8 and 10-11 above, and further in view of Jin et al. (Published 29 September 2018, Oral Infectious Diseases, in: Chen et al., Case Based Oral Mucosal Diseases, (Singapore, Springer Nature, 2018), pp. 1-26, PTO-892).
Liu-1 addresses claims 1, 6-8 and 10-11 as written above. Although, Liu-1 does not teach the medicament comprises (a) chlorhexidine, required in claim 19; and (b) vitamin C, vitamin B or both, required in claim 21.
However, in the same filed of endeavor of hand-foot-mouth disease (HFMD), with respect to limitations (a)-(b), Jin teaches a 7 year old female, see pg. 11, section 1.3 hand-foot-mouth disease, age; is diagnosed with hand-foot-mouth disease, see pg. 12, left column, diagnosis; and where there are little ulcers scattered on the oral mucosa, see pg. 12, left column, diagnosis basis.
Jin teaches the chief complaints included oral ulcers, see pg. 11, section 1.3 hand-foot-mouth disease, right column, chief complaints. Jin teaches various treatments associated with hand-foot-mouth disease, see pg. 12, right column, last paragraph of the column; including vitamin C tablets, vitamin B tablets; and a chlorhexidine solution used as a rinse solution, see pg. 13, left column, paragraph 1.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have included limitations (a)-(b) as taught by Jin above into the compositions and methods as taught by Liu-1 above as within the scope of the artisan as combining prior art elements according to known compositions and methods to yield predictable results.
One of ordinary skill in the art would have been motivated to treat the subject having an EV71 viral infection causing hand-foot-mouth disease as taught by Liu-1 above; as treatments using vitamin C, vitamin B and chlorhexidine for treating hand-foot-mouth disease are known in the art as taught by Jin above.
One of ordinary skill in the art would have had a reasonable expectation of success of including limitations (a)-(b) as taught by Jin above into the compositions and methods of Liu-1 as discussed above, as Liu-1 and Jin are both drawn to treating hand-foot-mouth disease; Jin teaches using vitamin C, vitamin B and chlorhexidine for treating hand-foot-mouth disease are known in the art; and Liu-1 teaches dosage forms of their composition includes solutions, tablets and powders as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(IX) Claims 1, 5-10 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Verma et al. (Published 01 August 2013, BMJ Case Reports, pp. 1-4, PTO-892) in view of Zhang et al. (Published 21 December 2012, Journal of Thoracic Disease, Vol. 4, Issue 6, pp. 617-623, PTO-892) and Naidu et al. (Published September-October 2004, Neoplasia, Vol. 6, Issue 5, pp. 423-431, PTO-892 mailed 05/01/2025) as evidenced by Xu et al. (Published 01 September 2011, Analytical Biochemistry, Vo. 419, Issue 2, pp. 323-332, PTO-892).
Regarding claims 1, 5-10 and 15, Verma teaches a case of primary oral tuberculosis (TB) with two intraoral non-healing ulcers present in a 34-year-old individual (e.g. a human, required in claim 10), see pg. 1, left column, background, paragraph 4. Verma teaches said individual had a non-healing ulcer on their left inner commissure and left labial vestibule, see pg. 1, right column, case presentation, paragraph 1.
Verma teaches antitubercular treatment was initiated, wherein the first phase included isoniazid, rifampin (e.g. rifampicin, required in claim 1, line 5), pyrazinamide and ethambutol; and a second phase of treatment consisted of isoniazid and rifampin daily for 2 months; where Verma teaches two weeks after initiation of the first phase of treatment tissue regeneration was evident in the area of the lesion (figure 1C,D) and in the following 2 weeks the lesion had almost resolved (figure 1E,F), see pg. 2, left-right column, treatment, paragraph 1.
Although, Verma does not teach wherein (a) the medicament comprises anemoside B4 as required in claim 1, line 4; (b) the oral ulcer is caused by chemotherapy, required in claim 1, line 3; and (c) the preparation, required in claims 6-9.
However, in the same field of endeavor of treating tuberculosis, with respect to limitation (a), Zhang teaches Pulsatilla chinensis can inhibit Mycobacterium tuberculosis (MTB) in vitro while enhancing immune function. It has also been found that Pulsatilla chinensis can suppress the hepatotoxicity of rifampicin and isoniazid and thus plays a protective role for the liver. Combined use of Pulsatilla chinensis, rifampin, and isoniazid can ensure their original efficacies and meanwhile eliminate their side effects. See pg. 621, left column, single traditional Chinese medicine, paragraph 1.
Additionally, as evidenced by Xu, Pulsatilla chinensis extract contains anemoside B4, see pg. 326, left column, preparation of Pulsatilla chinensis extract, paragraph 2.
Moreover, with respect to limitation (b), Naidu teaches chemotherapy induced oral mucositis complicating the treatment of cancer, see pg. 423, title. Naidu teaches within 1 week of therapy epithelial breakdown ultimately results in the ulcerative phase, see pg. 424, right column, phase III, lines 2-3.
Naidu teaches oral complications that arise with chemotherapy include mucositis (stomatitis) and bacterial or viral infection, see pg. 423, right column, introduction, paragraph 1, lines 9-11.
Naidu teaches the oral mucosa of cancer patients is colonized by a variety of potentially pathogenic microorganisms such as and including Gram-positive opportunistic bacteria, see pg. 429, left column, antimicrobial/antifungal/antiviral agents, paragraph 1.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the invention’s effective filing date to have included the oral ulcer is caused by chemotherapy into the method of Verma, as Naidu teaches chemotherapy induces oral mucositis, wherein ulcerations occur after 1 week of treatment; and teaches oral complications including bacterial infection which arises from chemotherapy treatment in cancer patients, wherein the oral mucosa of cancer patients are colonized by a variety of potentially pathogenic bacteria such as Gram-positive opportunistic bacteria, for example the patient infected with Mycobacterium tuberculosis causing primary oral tuberculosis manifesting a non-healing oral ulcer on the patient’s left inner commissure and left labial vestibule as taught by Verma as discussed above.
In addition, Zhang teaches Pulstilla chinensis can inhibit Mycobacterium tuberculosis (MTB) in vitro while enhancing immune function as discussed above. Thus, one of ordinary skill in the art would have been motivated to include the oral ulcer is caused by chemotherapy into the method of Verma above because anemoside B4 is the main saponin in Pulstilla chinensis as evidenced by Xu above.
Moreover, one of ordinary skill in the art would have had a reasonable expectation of success to have included the oral ulcer is caused by chemotherapy, as Naidu teaches bacterial infections occur as oral complications caused by chemotherapy treatment and allows the oral mucosa of cancer patients to be colonized by Gram-positive opportunistic bacteria as taught by Naidu above.
With respect to the limitation of the “preparations”, required in claims 6-9; the Examiner reasonably interprets the first and second phases of treatment taught by Verma above can be formulated as either an oral or a non-oral preparation as this type of limitation is well within the scope of the artisan; additionally, the therapeutic agents administered by Varma within the first and second phases were provided in milligrams (mg), see Varma, pg. 2, left-right column, treatment, paragraph; and thus the Examiner reasonably interprets any method of administration of the first and/or second phases can be prepared, for example as a tablet (e.g. an oral preparation) or as a solution for intravenous injection (e.g. required in claim 8) or for use as a rectal perfusion agent (e.g. required in claim 9). One of ordinary skill in the art would have been motivated to include these preparations in order to treat the patient of Verma as discussed above.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have included limitations (a)-(c) as taught by Zhang and Naidu as evidenced by Xu above as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to make the addition of limitation (a) as discussed above in order to treat the patient of Verma, as Zhang teaches combined use of Pulsatilla chinensis, rifampin, and isoniazid can ensure their original efficacies and eliminate their side effects by suppressing hepatotoxicity in the patient of Verma who is treated with rifampin and isoniazid in both the first and second phases to treat said patient’s oral tuberculosis as discussed above; and to have included limitation (b) as Naidu teaches chemotherapy induces oral mucositis and wherein bacterial infection is a known oral complications of chemotherapy treatment as discussed above. One of ordinary skill in the art would have had a reasonable expectation of success to have included limitations (a)-(c) into the method of Verma, as both Verma and Zhang are drawn to treating tuberculosis; Naidu teaches cancer patients treated with chemotherapy where the oral mucosa of said patients is colonized by a variety of potentially pathogenic microorganisms such as and including Gram-positive opportunistic bacteria, for example Mycobacterium tuberculosis which is the bacterial infection that causes tuberculosis as taught by Verma above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(X) Claims 2 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Verma et al. (Published 01 August 2013, BMJ Case Reports, pp. 1-4, PTO-892) in view of Zhang et al. (Published 21 December 2012, Journal of Thoracic Disease, Vol. 4, Issue 6, pp. 617-623, PTO-892) as evidenced by Xu et al. (Published 01 September 2011, Analytical Biochemistry, Vo. 419, Issue 2, pp. 323-332, PTO-892) as applied to claims 1, 5-10 and 15 above, and further in view of Li (Published 07 January 2009, CN-101337004-A, PTO-892, Using the NPL English Machine Translation).
Verma and Zhang as evidenced by Xu address claims 1, 5-10 and 15 as written above. Although, Verma and Zhang as evidenced by Xu do not teach (a) the recurrent oral ulcer, required in claim 2; and the medicament comprises (b) dexamethasone, required in claim 16; and (c) metronidazole, required in claim 17.
However, in the same field of endeavor of treating tuberculosis, with respect to limitations (a)-(c), Li teaches an oral ulcer powder comprising 10 parts of membranous milk vetch root, 4 parts of angelica root, 3 parts of bupleurum, 5 parts of Chinese wolfberry, 3 parts of glycyrrhiza uralensis, 0.4 parts of metronidazole and 0.75 parts of dexamethasone, see pg. 1, abstract.
Li teaches the oral ulcer powder has the advantages of simple components, low cost and ideal curative effect, and has comparatively obvious curative effect of curing long-term severe recurrent oral ulcer, see pg. 1, abstract.
Li exemplifies the main disease type of recurrent oral ulceration includes tuberculous ulcer, see pg. 2, paragraph 6.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have included the oral ulcer powder as taught by Li above into the treatment method as taught by Verma above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to treat the oral ulcers caused by a tuberculosis infection as taught by Verma above.
One of ordinary skill in the art would have had a reasonable expectation of success of including limitations (a)-(c) as taught by Li above into the treatment method as taught by Verma above, as both Verma and Li are both drawn to treating oral ulcers caused by tuberculosis; where Verma teaches their therapeutic agents were administered in milligrams as discussed above, and wherein the Examiner reasonably interprets agents taught by Verma above can be included in the dosage form of an oral powder as taught by Li above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(XI) Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Verma et al. (Published 01 August 2013, BMJ Case Reports, pp. 1-4, PTO-892) in view of Zhang et al. (Published 21 December 2012, Journal of Thoracic Disease, Vol. 4, Issue 6, pp. 617-623, PTO-892) and Li (Published 07 January 2009, CN-101337004-A, PTO-892, Using the NPL English Machine Translation) as evidenced by Xu et al. (Published 01 September 2011, Analytical Biochemistry, Vo. 419, Issue 2, pp. 323-332, PTO-892) as applied to claims 1-2, 5-10 and 15-17 above, and further in view of Calabrese et al. (Published 26 September 2013, International Journal of Pharmaceutics, Vol. 457, Issue 1, pp. 224-236, PTO-892).
Verma, Zhang and Li as evidenced by Xu address claims 1-2, 5-10 and 15-17 as written above. Although, Verma, Zhang and Li as evidenced by Xu do not teach wherein the medicament comprises montmorillonite, required in claim 18.
However, in the same field of endeavor of compositions comprising metronidazole, Calabrese teaches inorganic clay montmorillonite (MMT-K10) has a large specific surface area; exhibits good adsorb ability, cations exchange capacity, standout adhesive ability, and drug-carrying capability. Thus, MMT-K10 is a commonly used substance both as an excipient and active ingredient in pharmaceutical products. See pg. 225, left column, paragraph 1.
Calabrese exemplifies the use of MMT-K10 as a drug carrier for the antibiotic metronidazole, see pg. 232, right column, paragraph 3. Calabrese clearly suggests that the kind of interactions between the montmorillonite and the drug metronidazole (MNE) makes the MNE/MMTK10 complex very stable and the interaction of the clay with the MNE does not induce any change in the chemical nature of the antibiotics. Calabrese concludes these results could be fruitfully exploited for successfully prolonging the action of the drug at the desired site. See pg. 232, right column, paragraph 3.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated both the montmorillonite as taught by Calabrese above and the oral powder taught by Li above within the treatment method as taught by Verma above as combining prior art elements according to known compositions and methods to yield predictable results. One of ordinary skill in the art would have been motivated to include montmorillonite into the oral powder of Li in order to prolong the action of metronidazole at the desired site as taught by Calabrese; because the oral powder of Li contains metronidazole to treat recurrent oral tuberculous ulcers as taught by Li above; and wherein the Examiner respectfully notes can aid in alleviating tuberculous ulcers of the patient in the treatment method as taught by Verma as discussed above.
One of ordinary skill in the art would have had a reasonable expectation of success to have included the montmorillonite as taught by Calabrese above into the oral powder of Li discussed above for use in the method of Verma as discussed above; as Calabrese teaches MMT-K10 is a commonly used substance both as an excipient and active ingredient in pharmaceutical products; Calabrese teaches MMT-K10 may prolong the action of metronidazole at the desired site; and wherein the Examiner respectfully notes metronidazole is used by Li to treat recurrent oral tuberculous ulcers as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
(XII) Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Verma et al. (Published 01 August 2013, BMJ Case Reports, pp. 1-4, PTO-892) in view of Zhang et al. (Published 21 December 2012, Journal of Thoracic Disease, Vol. 4, Issue 6, pp. 617-623, PTO-892) as evidenced by Xu et al. (Published 01 September 2011, Analytical Biochemistry, Vo. 419, Issue 2, pp. 323-332, PTO-892) as applied to claims 1, 5-10 and 15 above, and further in view of Shamkuwar et al. (Published Year 2017, Advanced Biomedical Research, Vol. 6, Issue 1, pp. 1-6, PTO-892).
Verma and Zhang as evidenced by Xu address claims 1, 5-10 and 15 as written above. Although, Verma and Zhang as evidenced by Xu do not teach wherein the medicament comprises levamisole, required in claim 16.
However, in the same field of endeavor of treating tuberculosis, Shamkumar teaches levamisole as an adjuvant to short-course therapy in newly diagnosed pulmonary tuberculosis patients, see pg. 1, title.
Shamkumar teaches the efficacy of levamisole (LVM) (immunomodulator) as an adjuvant to chemotherapy of pulmonary tuberculosis patients, see pg. 1, abstract, background.
Shamkumar teaches all the patients 25 (100%) in the LVM group were sputum negative compared to 14 (56%) in placebo group by the end of 3 weeks. Additionally, within the LVM group, 24 (96%) and 11 (44%) patients in placebo group show radiological improvement at 2 months. See pg. 1, abstract, results.
Shamkumar concludes that adjuvant immunomodulation with levamisole has the potential of shortening the total duration of antitubercular therapy, see pg. 1, abstract, conclusion.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated levamisole as taught by Shamkumar above into the treatment method of Verma as discussed above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to incorporate levamisole as taught by Shamkumar above into the treatment method of Verma as discussed above in order to shorten the total duration of antitubercular therapy as taught by Shamkumar above. One of ordinary skill in the art would have had a reasonable expectation of success to have incorporated levamisole as taught by Shamkumar above into the treatment method of Verma as discussed above; as Verma and Shamkumar are both drawn to treating tuberculosis patients with antitubercular agents; and wherein as taught by Shamkumar above all patients in the levamisole group were sputum negative by the end of 3 weeks as compared to 56% in the placebo group as discussed above.
Thus, the claimed invention as whole would have been prima facie obvious over the combined teachings of the prior art.
Conclusion
No claims are allowed in this action.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARET J CREWS whose telephone number is (571)270-0962. The examiner can normally be reached Monday-Friday: 9:00am-5:30pm EST.
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