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 .
In view of the amendment, previous 112(b) rejection on claims 41 and 42 is hereby withdrawn.
THIS ACTION IS MADE FINAL. 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.
Claim Objections
Claim 35 is objected to because of the following informalities: applicant need to change “a suppository such as gelatine capsules or gelatine-free capsules,” to either --- a suppository, --- or --- a suppository gelatine capsule or a suppository gelatine-free capsule, --- (so as to make the scope of the claim more definite because it is unclear whether the limitation following the phrase “such as” are part of the claimed invention or not – see MPEP 2173.05(d)) . Appropriate correction is required.
Claim 44 is objected to because of the following informalities: on line 4, applicant need to insert --- and --- between “LSIL,” and “wherein”. On line 5, applicant need to insert --- also --- between “are” and “p16-positive”. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 16 and 19-44 are rejected under 35 U.S.C. 103 as being unpatentable over Fuchs (US 2013/0323328 A1) in view of Schmidt et al (“p16/Ki-67 Dual-Stain Cytology in the Triage of ASCUS and LSIL Papanicolaou Cytology”, Results from the European Equivocal or Mildly Abnormal Papanicolaou Cytology Study”, Cancer Cytopathology 2011, vol.119(3), pg.158-166) (with Huber et al (“Routine Treatment of Cervical Cytological Cell Changes”, Geburtsh Frauenheilk, 2016, vol.76, pg.1086-1091), which is cited here merely to support the Examiner’s assertion that PAP III and PAP IIID scores correspond to ASC-US, ASC-H, LSIL and HSIL according to the Bethesda classification).
Fuchs teaches (claim 14) the following:
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Thus, Fuchs teaches instant step of obtaining the pharmaceutical composition of claims 16 and 44. Fuchs further teaches (claim 15 and [0027]) that the pharmaceutical composition can be administered intravaginally. Thus, Fuchs teaches instant step of intravaginally administering instant pharmaceutical composition. After stating ([0006]) that it aims to provide means for the prevention and treatment of inflammations, dysplasias and/or carcinomas of the cervix, Fuchs teaches ([0018] and claim 28) that its composition is administered to a subject having a PAP score of PAP III and PAP IIID, and as evidenced by Huber (see pg.1090, right-hand column, last five lines), PAP III and PAP IIID scores correspond to ASC-US, ASC-H, LSIL and HSIL according to the Bethesda classification (Fuchs further teaches ([0018] and claim 27) that its inventive composition is also particularly effective in the treatment of cervical cell alterations (abnormalities) having a PAP score of ≥ PAP III or a CIN score of ≥CIN 1 (i.e., CIN 1, CIN 2, CIN 3)). Thus, Fuchs teaches instant patient having cervical cell abnormalities, which are ASC-US or LSIL.
With respect to instant limitation “wherein the cervical cell abnormalities are p16-positive and Ki-67-positive”, Fuchs does not explicitly teach that the subject having a PAP score of PAP III and PAP IIID (ASC-US, ASC-H, LSIL and HSIL) is also tested p16-positive and Ki-67-positive. Schmidt teaches (abstract) that women with ASC-US or LSIL who also test positive for p16/Ki-67 dual-stain cytology will have 92.2% or 94.2% chance, respectively, of developing CIN2+. Since Fuchs teaches that it aims to prevent and treat cervical cell abnormalities including ASC-US and LSIL (as well as cervical cell abnormalities having a PAP score of ≥ PAP III or a CIN score of ≥CIN 1), It would have been obvious to one skilled in the art to treat women with ASC-US or LSIL who test positive for p16/Ki-67 dual-stain cytology (i.e., women who have a very high chance of developing CIN2+ later and thus in need of preventing such progression) by administrating Fuchs’s pharmaceutical composition with a reasonable expectation of treating cervical cell abnormalities such as ASC-US and LSIL as well as effectively preventing or reducing progression of the cervical cell abnormalities (to more serious abnormalities, such as CIN2+) in the women (Fuchs’s table in Example 3 shows that 35 out of 45 patients went from a higher PAP score to a lower PAP score within 3-6months, 7 patients maintained their PAP score and 3 patients got worse).
Thus, Fuchs in view of Schmidt renders obvious instant claims 16, 19 and 44.
With respect to instant claims 20, 30 and 31, although Fuchs does not expressly state the limitations of these claims, it is the Examiner’s position that it would be common-sensical to administer Fuchs’s pharmaceutical composition to the women with ACS-US or LSIL who test positive for p16/Ki-67 dual-stain cytology until they become p16-negative and Ki-67 negative (as recited in claim 20), until the progression of the cervical cell abnormalities are reduced (as recited in claim 30) or until the cervical cell abnormalities are not detected any more (as recited in claim 31). Thus, Fuchs in view of Schmidt renders obvious instant claims 20, 30 and 31.
With respect to instant claims 21, 22 and 35, Fuchs teaches ([0013] and [0020]) that its composition is preferably in the form of a gel and can contain 0.005 g (5 mg) – 0.1 g (100 mg) of sodium selenite pentahydrate per 100 g of the gel. Since the gel contains about 97% water (see Example 1 in [0022]), the density of the gel is approximately 1g/ml. Therefore, 1 g of gel would be equivalent to 1 ml of the gel, which means that Fuchs’s composition contains 5 mg – 100 mg of sodium selenite pentahydrate per 100 ml of the gel. Since sodium selenite pentahydrate (Na2SeO3(H2O)5) has Mw of 263 g/mol and selenium has atomic weight of 79 g/mol, there is 30 wt.% of selenium in sodium selenite pentahydrate. Thus, 5 mg-100 mg of sodium selenite pentahydrate per 100 ml of the gel would be converted to 1.5 mg-30 mg of selenium per 100 ml of the gel, and this means that there is 0.075 mg – 1.5 mg of selenium per 5 ml of the gel. Such range overlaps with instant ranges of claims 21 and 22 (0.01-1.25 mg and 0.20-0.30 mg) for the total selenium content per 5 ml of the pharmaceutical composition, thus rendering instant ranges prima facie obvious. In the case “where the [claimed] ranges overlap or lie inside ranges disclosed by the prior art,” a prima facie case of obviousness would exist which may be overcome by a showing of unexpected results, In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Thus, Fuchs in view of Schmidt renders obvious instant claims 21, 22 and 35.
With respect to instant claims 23-29, Fuchs teaches ([0023]-[0027]) that 5 ml of sodium selenite gel is administered intravaginally once per day for 90 days and that the administration is to be discontinued during menstruation, and as already stated above, 5 ml of sodium selenite gel contains 0.07 mg-1.5 mg of selenium. This means that per application, the total selenium dose would be 0.07 mg-1.5 mg, and this range overlaps with instant ranges (0.01-1.25 mg or 0.20 mg-0.30 mg per application) of claims 23-24 for the amount of the total selenium dose per application. Thus, Fuchs in view of Schmidt renders obvious instant claims 23-29.
With respect to instant claims 32-34, since Schmidt already teaches that women with ASC-US who test positive for p16/Ki-67 have a 92.2% chance of developing CIN2+ later if untreated, the progressions as listed in claims 32-34 would be obvious to one skilled in the art. Thus, Fuchs in view of Schmidt renders obvious instant claims 32-34.
With respect to instant claims 36, 38 and 39, Fuchs teaches (Example 1 in [0022]) a gel composition comprising sodium selenite pentahydrate, citric acid and silicon dioxide. Thus, Fuchs in view of Schmidt renders obvious instant claims 36, 38 and 39.
With respect to instant claims 37 and 43, Fuchs teaches (claim 23) that its pharmaceutical composition has a pH of 2.5 – 4.0. Thus, Fuchs in view of Schmidt renders obvious instant claims 37 and 43 (all the limitations of claim 43 other than the pH limitation were already discussed above).
With respect to instant claim 40, Fuchs teaches ([0008]) that its inventive composition is suitable for both HPV-induced and non-HPV-induced disorders of the uterus and that this is of great practical significance as the detection (or specification) of the HPV is often omitted in gynecological practices because the positive detection of an HPV infection often has no influence on subsequent therapeutic decisions. Thus, it would be obvious to administer Fuchs’s composition to a patient with ASC-US or LSIL who test positive for p16/Ki-67 dual-stain cytology even when the HPV infection status of the cervix uteri of the patient is unknown or not determined. Thus, Fuchs in view of Schmidt renders obvious instant claim 40. With respect to instant claims 41 and 42, it is the Examiner’s position that it is obvious (and common sensical) that Fuchs’s pharmaceutical composition and the treatment using such composition would be more efficient if the patient did not have other complications, such as cancer or chronic viral disease other than HPV infection or is not immunosuppressed. Thus, it would be obvious to one skilled in the art to administer Fuchs’s pharmaceutical composition to a patient with ASC-US or LSIL who test positive for p16/Ki-67, but not having cancer, chronic viral disease other than HPV infection or is not immunosuppressed with a reasonable expectation of treating ASC-US or LSIL and effectively preventing or reducing progression of the cervical cell abnormalities (to more serious abnormalities, such as CIN2+) in the patient. Thus, Fuchs in view of Schmidt renders obvious instant claims 41 and 42.
Response to Arguments
(I) Applicant’s argument of unexpected results (presented on pg.6-10 of REMARKS) were carefully considered but was not found to be persuasive. First, with respect to the data with respect to LSIL, in which the rate of remission plus regression after 6 months being numerically higher for the p16/Ki-67 double-positive subgroup than for the general LSIL baseline patient population treated with the active composition, applicant argue that this result is particularly surprising because one skilled in the art would have expected p16/Ki-67 positive lesions to be more advanced, more persistent and thus significantly more difficult to treat and less likely to regress compared to p16/Ki-67 negative lesions. However, Fuchs already states in [0018] that its inventive composition has “surprisingly proved to be particularly effective in the treatment of cervical cell alterations having a PAP score of ≥PAP III and/or CIN score of ≥CIN 1” (i.e., CIN 1, CIN 2 and CIN 3). Thus, one skilled in the art studying Fuchs would expect that Fuchs’s pharmaceutical composition should be able to treat even the more advanced and more difficult to treat (and less likely to regress) lesions such as p16/Ki-67 positive lesions. Thus, the superior result shown for LSIL patients in p16/Ki-67 double positive subgroup (i.e., remission + regression being 87% compared to 79.7% for the general LSIL baseline patient population) is nothing unexpected. Secondly, with respect to the rate of remission + regression for the p16/Ki-67 double-positive subgroup being numerically slightly lower (at 69%) than the overall ASC-US baseline patient population (having remission + regression of 76.2%), applicant argue that such slightly lower percentage can be readily explained by spontaneous regression in these “easier-to-resolve” cases (ASC-US) and argue that achieving a success rate that is still remarkably high (69%) in the p16/Ki-67 positive subgroup is profoundly unexpected as the expectation in the art would have been a substantially lower success rate for this subgroup. However, as discussed above, Fuchs already states that its inventive composition has “surprisingly proved to be particularly effective in the treatment of cervical cell alterations having a PAP score of ≥PAP III and/or CIN score of ≥CIN 1” (i.e., CIN 1, CIN 2 and CIN 3). Thus, one skilled in the art would expect that Fuchs’s pharmaceutical composition should be able to treat even the more advanced and more difficult to treat (and less likely to regress) lesions such as p16/Ki-67 positive lesions. Furthermore, the control arm (i.e., without treatment with the vaginal gel) results shown in Major 2021 and Major 2021(a) contradict applicant’s argument about spontaneous regression because the remission + regression rate of the overall ASC-US baseline patient population is 25% (see Figure.2 of Major 2021) while the p16/Ki-67 double-positive subgroup showed a remission + regression rate of 26% (see Table 3 of Major 2021(a)). If applicant’s argument of spontaneous regression applied, then the remission + regression rate for the overall ASC-US baseline patient population should be higher that the remission + regression rate for the p16/Ki-67 double-positive subgroup. Thirdly, applicant argue that the results shown in Major 2021 and Major 2021(a) represent an unexpected technical effect to a POSTA, at least because p16/Ki-67 positivity is a hallmark of a cervical lesion having undergone an oncogenic transformation and hence more difficult to treat by non-invasive methods as presumed b a POSITA without knowledge of present invention and “as acknowledged by the Office: ‘it is the Examiner’s position that it is obvious . . . that Fuchs’s pharmaceutical composition and treatment using such composition would be more efficient if the patient did not have cancer or chronic viral disease and it not immunosuppressed’ ”. However, the Examiner does not understand the point applicant are trying to make. In rejecting instant claims 41 and 42, since it is obvious (and common sensical) that Fuchs’s treatment using its composition would be more efficient if the patient did not have other complications (such as cancer or chronic viral disease other than HPV infection or is not immunosuppressed), the Examiner asserted that it would be obvious to one skilled in the art to administer Fuchs’s pharmaceutical composition to a patient with ASC-US or LSIL who test positive for p16/Ki-67, but not having cancer, chronic viral disease other than HPV infection or is not immunosuppressed. Making such assertion is not the same as acknowledging that the results shown in Major 2021 and Major 2021(a) represent an unexpected technical effect to a POSTA because p16/Ki-67 positivity is a hallmark of a cervical lesion having undergone an oncogenic transformation and hence more difficult to treat by non-invasive methods (besides, in the study shown in Major 2021 and Major 2021(a), prospective subjects with those conditions were also excluded from the clinical trials – see Major 2021(a), pg.2, right-hand column, last paragraph and pg.3, left-hand column, 1st paragraph).. As already discussed above, Fuchs already teaches in that its inventive composition has “surprisingly proved to be particularly effective in the treatment of cervical cell alterations having a PAP score of ≥PAP III and/or CIN score of ≥CIN 1” (i.e., CIN 1, CIN 2 and CIN 3). Thus, one skilled in the art would expect that Fuchs’s pharmaceutical composition should be able to treat even the more advanced and more difficult to treat (and less likely to regress) lesions such as p16/Ki-67 positive lesions. Lastly, applicant argue that present application show that both groups of patients (p16/Ki-67 negative or p16/Ki-67 positive at baseline) benefited from the inventive therapy also with respect to p16/Ki-67 status (by maintaining the status of being p-16/Ki-67 negative or by changing the status back to p16/Ki-67 negative). Applicant argue that it was surprising that for the group of patients who were p16/Ki-67 positive at base line (Fig.4B), the percentage of patients for whom the inventive therapy achieved a benefit with respect to p16/Ki-67 status during the observation period was much larger, when comparing the respective active arm to the respective control arm. However, the Examiner believes that the result shown in Fig.4B is not anything surprising because one skilled in the art would expect that the remission + regression rate for untreated patients who are p16/Ki-67 positive would be very low since they have a very high chance of progressing to CIN2+. Thus, the greater benefit shown in the active arm which applicant is referring to in Fig.4B is because applicant is subtracting a very low number of the control arm from a high number in the active arm.
(II) Applicant’s argument of a lack of motivation to arrive at the claimed invention is also found to be unpersuasive. Applicant argue that staring from the broad disclosure of Fuchs treating patients with PAP III/IIID score, would lack a motivation to select a patient with a p16 positive and Ki-67 positive ASC-US or LSIL cervical cell abnormality. Applicant argue that although Schmidt examines the expression pattern of p16 and K-i67 in cervical neoplasia, it showed that only 34.9% of the samples were double positive and makes no teaching or suggestion that this patient population would be responsive to the claimed method. Applicant argue that a POSITA would lack a motivation to treat this patient population with a reasonable expectation of success at least because the p16/Ki-67 positive group is at higher risk (as taught by Schmidt) and thus inherently more difficult to treat. Applicant further argue that disclosure that cervical neoplasia can be double positive for p16 and Ki-67 is not a reason why a POSTA would select the specific patient population for treatment. The Examiner disagrees. First of all, Schmidt was cited for the teaching that women with ASC-US or LSIL who also test positive for p16/Ki-67 dual-stain cytology will have 92.2% or 94.2% chance, respectively, of developing CIN2+ later. Secondly, Fuchs teaches that it aims to prevent and treat cervical cell abnormalities including ASC-US and LSIL. Fuchs also teaches that its inventive composition is particularly effective in the treatment of cervical cell alterations (abnormalities) having a PAP score of ≥ PAP III or a CIN score of ≥CIN 1 (i.e., CIN 1, CIN 2, CIN 3)). Since women with ASC-US or LSIL who test positive for p16/Ki-67 dual-stain cytology have a very high chance of developing CIN2+ later (according to Schmidt) and thus are in urgent need of preventing such progression, it would be obvious to one skilled in the art to administer Fuchs’s pharmaceutical composition with a reasonable expectation of treating cervical cell abnormalities such as ASC-US and LSIL as well as effectively preventing or reducing progression of the cervical cell abnormalities (to more serious abnormalities, such as CIN2+) in the women (Fuchs’s table in Example 3 shows that 35 out of 45 patients went from a higher PAP score to a lower PAP score within 3-6months, 7 patients maintained their PAP score and 3 patients got worse).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SIN J. LEE whose telephone number is (571)272-1333. The examiner can normally be reached on M-F 9 am-5:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Kwon can be reached on 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
December 26, 2025