DETAILED ACTION
This office action is in response to applicant’s filing dated September 22, 2025.
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 .
Status of Claims
Claims 1, 2, 4, 6, 7, 9, 10, 13-15, and 22-30 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed September 22, 2025. Acknowledgement is made of Applicant’s amendment of claim 1. Claims 3, 5, 8, 11, 12, 16-21, and 31-37 were previously canceled.
Applicants elected without traverse breast cancer as the elected cancer species; 1,25-dihydroxyvitamin D3 as the vitamin D compound species; a formulation species comprising 1,25-dihydroxyvitamin D3 as the vitamin D compound species, and a vehicle comprising propylene glycol and anhydrous ethanol in the reply filed on May 22, 2023. The requirement is still deemed proper. Claim 25 remains withdrawn.
Claims 1, 2, 4, 6, 7, 9, 10, 13-15, and 22-30 are presently under examination as they pertain to the elected species: breast cancer, calcitriol, propylene glycol and anhydrous ethanol.
Priority
The present application is a Continuation of US Application No. 16/424,037 filed on May 28, 2019, which is a Continuation of US Application No. 14/953,334 filed on November 28, 2015, which is a Continuation of PCT/US2014/040084 filed on May 29, 2014, which claims benefit of US Provisional Application No. 61/828,448 filed on May 29, 2013. The effective filing date of the instant application is May 29, 2013.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Modified Objections and/or Rejections
Modifications Necessitated by Claim Amendment
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1, 2, 4, 6, 7, 9, 10, 22-24, and 26-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jimenez et al (US 5,486,509, hereinafter referred to as Jimenez ‘509, cited in a previous Office Action) in view of Pitre et al (EP 1,952,808 A2, cited in a previous Office Action) and Dr. Mercola® Premium Supplements (http://products.mercola.com/vitamin-d-spray/, Internet Archive Wayback Machine date, March 3, 2011, cited in a previous Office Action) as evidenced by Sunshine Mist™ Vitamin D Spray product label obtained from the archived webpage: (https://web.archive.org/web/20110303080308/http://mercola.fileburst.com/PDF/product-labels/vitaminD-spray-label-v100.pdf, cited in a previous Office Action).
Regarding claims 1 and 27-30, Jimenez ‘509 teaches a method of reducing chemotherapy-induced alopecia comprising administering to a patient undergoing chemotherapy with at least one chemotherapeutic agent 1,25-dihydroxyvitamin D3 in an effective amount (claim 29); wherein said 1,25-dihydroxyvitamin D3 is administered topically (claim 30). Jimenez teaches a solution of 2-100 μg/ml of 1,25-dihydroxyvitamin D3 in absolute ethanol can be prepared and 3-5 ml of that solution applied directly to the scalp at various points with a dropper followed by scalp massage for 3-5 min to ensure even distribution.
Jimenez ‘509 further teaches when chemotherapy is involved, this treatment is, advantageously, administered once or twice daily beginning 5-8 days prior to initiation of chemotherapy and continued through the course of chemotherapy. Administering to a patient undergoing chemotherapy with at least one chemotherapeutic agent reads on selecting a human subject having cancer who is receiving chemotherapy.
Jimenez ‘509 does not explicitly teach the composition is topically administered using a metered spray unit.
However, Pitre teaches a composition comprising calcitriol that is sprayable (claim 1) wherein the calcitriol is in an amount of between 0.0001 and 20% (claim 2). Pitre teaches the composition is preferably in a dosing spray bottle, for which the application area and dose characteristics are controlled and reproducible; the spray device used consists of a bottle equipped with a 25µl dosing valve [0044]. This reads on a metered spray unit. Pitre further teaches that the composition is suitable for producing a medicinal product intended for treating alopecia, in particular alopecia caused by chemotherapy or radiation [0045]. The Examiner notes that 1,25-dihydroxyvitamin D3 is equivalent to calcitriol.
As such, since Jimenez ‘509 teaches a method of reducing chemotherapy-induced alopecia comprising administering to a patient undergoing chemotherapy with at least one chemotherapeutic agent 1,25-dihydroxyvitamin D3 in an effective amount, and since Pitre teaches a composition comprising calcitriol formulated in a spray composition for use in a metered spray bottle which is useful for treating alopecia of various origins, in particular alopecia caused by chemotherapy, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize a metered spray unit to deliver composition taught by Jimenez topically to the scalp for treating alopecia induced by chemotherapeutic agents since the prior art teaches this as a method of administration for administering calcitriol for treating alopecia induced by chemotherapeutic agents.
Regarding the amounts of vitamin D of instant claims 1, 6, 7, and 10, Jimenez ‘509 teaches a solution of 2-100 μg/ml of 1,25-dihydroxyvitamin D3 in absolute ethanol can be prepared and 3-5 ml of that solution applied directly to the scalp once daily (col 4, lines 20-26). 3-5 ml of 2-100 μg/ml 1,25-dihydroxyvitamin solution once daily is equivalent to a total daily dose of 6-10 μg to about 300-500 μg 1,25-dihydroxyvitamin. 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).
Regarding the limitation the pharmaceutical composition is administered in an about 1.0 mL dose (instant claim 1) or 0.25 mL (instant claim 9), Jimenez ‘509 teaches applying 3-5 ml and Pitre teaches a spray bottle with a 25µl dosing valve. It would have been prima facie for one of ordinary skill in the art to optimize the spray dosing bottle to administer a composition in the desired dose in an amount of between 25µl to 3-5 ml as taught by the prior art. Moreover, Dr. Mercola Premium Supplements Sunshine Mist™ Vitamin D Spray product label teaches serving size is 6 sprays (approximately 0.78 mL) and that the container contains approximately 32 servings. Thus, Dr. Mercola Premium Supplements teaches a metered pump designed to dispense 0.13-ml, 6 times, and that the container contains about 192 sprays.
As such, since Jimenez ‘509 teaches a topical solution for inhibiting alopecia induced by chemotherapeutic agents comprising 1,25-dihydroxyvitamin D3, propylene glycol and ethyl alcohol wherein 1,25-dihydroxyvitamin D3 is administered in a concentration of 2-100 μg/ml, since Pitre teaches a composition comprising calcitriol formulated in a spray composition for use in a metered spray bottle equipped with a 25µl dosing valve, and since Dr. Mercola Premium Supplements teaches a metered dose spray composition comprising vitamin D wherein the serving size is 6 sprays (approximately 0.78 mL) in a container containing about 32servings, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize the dispense dose, number of spray doses, and amount of dispenses (sprays) the container holds taught by Dr. Mercola Premium Supplements as a starting point for optimizing the spray dispenser to deliver the optimum dose of the vitamin D derivative calcitriol for supplementing the subject without overdosing.
Regarding the limitation directed to administering the composition to each of the four quadrants of the scalp, it would have been prima facie obvious to one of ordinary skill in the art to evenly distribute the composition across the scalp in order to evenly treat the scalp to reduce chemotherapy induced alopecia evenly throughout the scalp.
Regarding claims 2 and 4, Jimenez ‘509 teaches when chemotherapy is involved, this treatment is, advantageously, administered once or twice daily beginning 5-8 days prior to initiation of chemotherapy.
Regarding claims 22 and 26, the wherein limitations of these claims, are considered to simply express the intended result of a process step positively recited, which is not given patentable weight (See MPEP 9111.o4: [T]he court noted (quoting Minton v. Nat'lAss'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQgd 1614, 169o (Fed. Cir. 9oo3)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.'" Hoffer v. Microsoft Corp., 405 F.3d 1396, 1399, 74 USPQgd 1481, 1483 (Fed. Cir. 9oo5).).
Taken together, all this would result in the practice of the method of claims 1, 2, 4, 6, 7, 9, 10, 22, and 26-30 with a reasonable expectation of success.
Regarding claim 23, Jimenez ‘509 does not explicitly teach the composition is anhydrous. However, as set forth above, Pitre teaches a composition comprising calcitriol formulated in a spray composition for use in a metered spray bottle which is useful for treating alopecia of various origins, in particular alopecia caused by chemotherapy, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize a metered spray unit to deliver composition taught by Jimenez ‘509 topically to the scalp for treating alopecia induced by chemotherapeutic agents since the prior art teaches this as a method of administration for administering calcitriol for treating alopecia induced by chemotherapeutic agents. Pitre further teaches the topical-application composition may be provided in anhydrous form [0041]. It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the topical spray composition comprising vitamin D in an anhydrous form as taught by Pitre with a reasonable expectation of success since the prior art teaches this is a suitable form for formulating a topical-application composition comprising vitamin D.
Taken together, all this would result in the method of claim 23 with a reasonable expectation of success.
Regarding claim 24, Jimenez ‘509 teaches a topical solution comprising 0.0002-0.1% 1,25-dihyroxyvitamin D3, propylene glycol 10%,30% propylene glycol dicaprylate/dicaprate, 0.05% butylated hydroxytoluene (BHT), 0.05% butylated hydroxyanisole, and ethyl alcohol, absolute q.s. to 100% (see Example VIII, col 9). Thus, the composition taught by Jimenez ‘509 comprises 10 % propylene glycol and 60% absolute ethanol. It would have been obvious to one of ordinary skill in the art to utilize the amounts of propylene glycol and absolute ethanol taught by Jimenez ‘509 as a starting point for optimizing the amounts of propylene glycol and absolute ethanol for use in formulating a composition comprising vitamin D for use in a method of reducing chemotherapy-induced alopecia because the prior art teaches these amounts are suitable for formulating a topical composition comprising vitamin D and because component amounts are result-effective variables, i.e. a variable that achieves a recognized result. Therefore, the determination of the optimum or workable amounts would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Taken together, all this would result in the method of claim 24 with a reasonable expectation of success.
Claims 13-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jimenez et al (US 5,486,509, hereinafter referred to as Jimenez ‘509, cited in a previous Office Action) in view of Pitre et al (EP 1,952,808 A2, cited in a previous Office Action) and Dr. Mercola® Premium Supplements (http://products.mercola.com/vitamin-d-spray/, Internet Archive Wayback Machine date, March 3, 2011, cited in a previous Office Action) as evidenced by Sunshine Mist™ Vitamin D Spray product label obtained from the archived webpage: (https://web.archive.org/web/20110303080308/http://mercola.fileburst.com/PDF/product-labels/vitaminD-spray-label-v100.pdf, cited in a previous Office Action) as applied to claims 1, 2, 4, 6, 7, 9, 10, 22-24, and 26-30 above, and further in view of Breastcancer.org https://www.breastcancer.org/research-news/20100602b, published online June 2, 2010, cited in a previous Office Action).
Jimenez ‘509, Pitre, and Dr. Mercola Premium Supplements Sunshine Mist™ Vitamin D Spray product label teach all the limitations of claims 13-15, except wherein the subject has breast cancer. Jimenez does teach pretreatment with vitamin D3 provided protection from chemotherapy induced alopecia from Adriamycin and Cytoxan combination (Table II).
Moreover, Breastcancer.org teaches a study suggests that treating early-stage breast cancer with two common chemotherapy medicines followed by a third (doctors call this a sequential approach) has some advantages compared to giving two or three chemotherapy medicines at the same time; the women were treated with two or three common chemotherapy medicines which included Adriamycin and Cytoxan.
It would have been obvious to one of ordinary skill in the art to utilize the method of reducing chemotherapy-induced alopecia suggested by Jimenez ‘509 and Pitre in a subject having breast cancer treated with Adriamycin and Cytoxan since the prior art teaches pretreatment with vitamin D3 provided protection from chemotherapy induced alopecia from Adriamycin and Cytoxan combination and Adriamycin and Cytoxan combination is a common chemotherapy for breast cancer, resulting in the practice of the method of claims 13-15 with a reasonable expectation of success.
Claims 1, 2, 4, 6, 7, 9, 10, 13-15, 22-24, and 26-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jimenez et al (US 2011/0059917 A1, hereinafter referred to as Jimenez ‘917, cited in a previous Office Action) in view of Pitre et al (EP 1,952,808 A2, cited in a previous Office Action) and Dr. Mercola® Premium Supplements (http://products.mercola.com/vitamin-d-spray/, Internet Archive Wayback Machine date, March 3, 2011, cited in a previous Office Action) as evidenced by Sunshine Mist™ Vitamin D Spray product label obtained from the archived webpage: (https://web.archive.org/web/20110303080308/http://mercola.fileburst.com/PDF/product-labels/vitaminD-spray-label-v100.pdf, cited in a previous Office Action).
Regarding claims 1, 2, 22-24, and 26-30, Jimenez ‘917 teaches a method of preventing or treating alopecia in an individual, comprising topically administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a vitamin D compound formulated to be delivered to epidermis while substantially avoiding dermis delivery (claim 1) wherein the pharmaceutical composition comprises about 40% (w/w) propylene glycol and about 60% (w/w) anhydrous absolute ethanol (200 proof, U.S.) (claim 2); wherein the vitamin D compound is 1,25-dihydroxyvitamin D3 (claim 5); wherein the alopecia is chemotherapy-induced alopecia (CIA) (claim 15); wherein alopecia has not commenced in the individual (claim 20), wherein the individual is undergoing or about to undergo chemotherapy (claim 21); wherein the pharmaceutical composition is administered to the individual prior to chemotherapy or concurrent with chemotherapy (claim 22); wherein the pharmaceutical composition does not substantially reduce the efficacy of chemotherapy (claim 24). Jimenez ‘917 teaches the composition can be formulated for topical administration in a spray [0269].
Jimenez ‘917 does not explicitly teach the composition is topically administered using a metered spray unit.
However, Pitre teaches a composition comprising calcitriol that is sprayable (claim 1) wherein the calcitriol is in an amount of between 0.0001 and 20% (claim 2). Pitre teaches the composition is preferably in a dosing spray bottle, for which the application area and dose characteristics are controlled and reproducible; the spray device used consists of a bottle equipped with a 25µl dosing valve [0044]. This reads on a metered spray unit. Pitre further teaches that the composition is suitable for producing a medicinal product intended for treating alopecia, in particular alopecia caused by chemotherapy or radiation [0045]. The Examiner notes that 1,25-dihydroxyvitamin D3 is equivalent to calcitriol.
As such, since Jimenez ’97 teaches a method of preventing chemotherapy-induced alopecia comprising administering a therapeutically effective amount of a vitamin D compound to a patient undergoing or about to undergo chemotherapy, and since Pitre teaches a composition comprising calcitriol formulated in a spray composition for use in a metered spray bottle which is useful for treating alopecia of various origins, in particular alopecia caused by chemotherapy, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize a metered spray unit to deliver composition taught by Jimenez topically to the scalp for treating alopecia induced by chemotherapeutic agents since the prior art teaches this as a method of administration for administering calcitriol for treating alopecia induced by chemotherapeutic agents.
Regarding the amounts of vitamin D of instant claims 1, 6 and 7, Jimenez ‘917 teaches in human subjects, a total dose of calcitriol (or other equivalent amount of vitamin D compounds) of about 2.5 μg, 5 μg, 10 μg, 25 μg, 50 μg, 75 μg, or 100 μg may be used. Regarding claim 10, Jimenez ‘917 teaches the concentration of the vitamin D compound in the topical formulation is about 0.1, 0.2, 0.5, 1.0, 2, 3, 5, 10, 20, 30, 50, 75, 100, 150, 200, or 400 μg/mL. 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).
Regarding the limitation the pharmaceutical composition is administered in an about 1.0 mL dose (instant claim 1) or 0.25 mL (instant claim 9), Jimenez ‘917 teaches applying amounts of 5.07, 10.31, and 55.34 µg/mL administered at a dose volume of 2.1 mL [0451] ml and Pitre teaches a spray bottle with a 25µl dosing valve. Moreover, Dr. Mercola Premium Supplements Sunshine Mist™ Vitamin D Spray product label teaches serving size is 6 sprays (approximately 0.78 mL) and that the container contains approximately 32 servings. Thus, Dr. Mercola Premium Supplements teaches a metered pump designed to dispense 0.13-ml, 6 times, and that the container contains about 192 sprays.
As such, since Jimenez ‘917 teaches a topical solution for inhibiting alopecia induced by chemotherapeutic agents comprising 1,25-dihydroxyvitamin D3, propylene glycol and ethyl alcohol wherein 1,25-dihydroxyvitamin D3 is administered in a concentration of 0.1, 0.2, 0.5, 1.0, 2, 3, 5, 10, 20, 30, 50, 75, 100, 150, 200, or 400 μg/mL at a dose volume of 2.1 mL, since Pitre teaches a composition comprising calcitriol formulated in a spray composition for use in a metered spray bottle equipped with a 25µl dosing valve, and since Dr. Mercola Premium Supplements teaches a metered dose spray composition comprising vitamin D wherein the serving size is 6 sprays (approximately 0.78 mL) in a container containing about 32 servings, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize the dispense dose, number of spray doses, and amount of dispenses (sprays) the container holds taught by Dr. Mercola Premium Supplements as a starting point for optimizing the spray dispenser to deliver the optimum dose of the vitamin D derivative calcitriol for supplementing the subject without overdosing. Regarding the limitation directed to administering the composition to each of the four quadrants of the scalp (instant claim 9), it would have been prima facie obvious to one of ordinary skill in the art to evenly distribute the composition across the scalp in order to evenly treat the scalp to reduce chemotherapy induced alopecia evenly throughout the scalp.
Regarding claims 2 and 4, Jimenez ‘917 teaches the vitamin D compounds of the invention is topically administered to the scalp twice daily each day for two consecutive weeks prior to the commencement of chemotherapy in order to prevention or reduce the severity of any CIA that may occur upon commencement of chemotherapy [0172].
Taken together, all this would result in the practice of the method of claims 1, 2, 4, 6, 7, 9, 10, 22-24, and 26-30 with a reasonable expectation of success.
Regarding claims 13-15, Jimenez ‘917 teaches the chemotherapy includes gemcitabine (claim 26) and Gemcitabine is used in the treatment of various carcinomas, including breast cancer [0357]. It would have been obvious to one of ordinary skill in the art to utilize the method of reducing chemotherapy-induced alopecia suggested by Jimenez ‘917 and Pitre in a subject having breast cancer treated with gemcitabine since the prior art teaches gemcitabine is a chemotherapeutic used to treat breast cancer, resulting in the practice of the method of claims 13-15 with a reasonable expectation of success.
Response to Arguments
Jimenez, Pitre, Dr. Mercola and Sunshine Mist
Applicant argues:
The claims as currently amended require a relatively high daily dose of the vitamin D compound, i.e. a total daily dose of about 10-100 µg of the vitamin D compound. It was known in the art at the time of filing of the present application that administration of Vitamin D compounds (e.g., calcitriol) at relatively high daily doses may cause adverse effects such as hypercalcemia. Wingerchuk et al. describes a study in which multiple sclerosis patients were administered a calcitriol dose of 2.5 µg/day by oral administration and report that 2 of 13 patients exhibited mild, asymptomatic hypercalcemia that required temporary dose adjustment to 1.5 µg/day and 2.0 µg/day, and that two patients withdrew from the study because of symptomatic hypercalcaemia including headache and abdominal pain. Applicant has surprisingly found that administration of calcitriol to the scalp by the particular dosing method required by the present claims (i.e., topically administering the pharmaceutical composition to the scalp of the subject using a metered spray unit, wherein the pharmaceutical composition comprises the vitamin D compound at a concentration of 5-20 µg/mL, and the pharmaceutical composition is administered in an about 1.0 mL dose and at a total daily dose of about 10-100 ug of the vitamin D compound) resulted in no severe treatment-related adverse events. The safety and efficacy of the particular dosing method required by the present claims as demonstrated by Applicant would not have been expected from the combined teachings of Jimenez, Pitre, Dr. Mercola and Sunshine Mist.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
MPEP 716.02(d) states:
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). In the instant case, in a review of the declaration, the Examiner notes that calcitriol was administered in amounts of 5, 10, 20, 40, 60 and 80 µg/ml twice daily or a daily dose of 10, 20, 40, 80, 120, and 160 µg. Thus, amounts outside the claimed amounts were tested (120 and 160 µg). The declaration does not appear to establish that the amounts tested outside the claim range showed different results. Thus, the data provided is not commensurate in scope with the claims and does not provide sufficient evidence to establish the criticality of the claimed range. Moreover, as evidenced by instant claim 9, which depends on and thus further limits the limitations of claim 1, the instant application clearly contemplates divided doses (i.e. dividing the 1 mL dose over multiple applications to the 4 quadrants of the head). Applicant has not provided any evidence to establish that the application of 1mL dose in single or divided doses possess unexpected properties.
As set forth above, Jimenez ‘509 teaches a method of reducing chemotherapy-induced alopecia comprising topically administering to a patient undergoing chemotherapy a therapeutically effective amount of 1,25-dihydroxyvitamin D3. As set forth above, Pitre teaches a composition comprising calcitriol formulated in a spray composition for use in a metered spray bottle which is useful for treating alopecia of various origins. Thus, it is not unexpected that topically administering calcitriol with a metered spray device would be effective for treating chemotherapy-induced alopecia. Moreover, as set forth above, Jimenez ‘509 teaches a solution of 2-100 μg/ml of 1,25-dihydroxyvitamin D3 in absolute ethanol can be prepared and 3-5 ml of that solution applied directly to the scalp once daily (col 4, lines 20-26). 3-5 ml of 2-100 μg/ml 1,25-dihydroxyvitamin solution once daily is equivalent to a total daily dose of 6-10 μg to about 300-500 μg 1,25-dihydroxyvitamin. 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).
Applicant argues:
While Jimenez describes the use of Vitamin D3 to prevent or treat alopecia, and generally discloses both topical administration and administration by injection, and a broad range of doses, Jimenez fails to demonstrate the safety or efficacy of the relatively high topical daily doses required by the present claims, i.e., a total daily dose of about 10-100 µg of the Vitamin D compound by topical administration, in a human subject. Instead, the examples of Jimenez describe much lower topical doses of the Vitamin D3 compound, e.g., 0.1 µg or 0.2 µg in the animal models described therein (see Example V). Thus, considering the teachings of Wingerchuk et al. that a calcitriol dose of 2.5 µg/day by oral administration resulted in hypercalcemia, a person of ordinary skill in the art reading Jimenez would not have reasonably expected that a total daily dose of about 10-100 µg of a Vitamin D compound by topical administration would result in safe and effective prevention of alopecia in a human subject, as demonstrated by Applicant. Thus a person of ordinary skill in the art, considering the teachings of Wingerchuk et al. that Vitamin D compounds may have toxic effects, would have been motived by the teachings of Jimenez to use lower doses of a Vitamin D compound to minimize systemic absorption and limit protection from alopecia to the site of application, not the relatively high topical total daily dose of about 10-100 µg of a Vitamin D compound required by the present claims.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
The Examiner notes that in Wingerchuk the calcitriol was administered orally. Thus, Wingerchuk does not provide any insight to the safety and/or efficacy of doses administered topically.
Moreover, MPEP 2123.II. states:
Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
In the instant case, as set forth above, Jimenez ‘509 teaches a solution of 2-100 μg/ml of 1,25-dihydroxyvitamin D3 in absolute ethanol can be prepared and 3-5 ml of that solution applied directly to the scalp once daily (col 4, lines 20-26). 3-5 ml of 2-100 μg/ml 1,25-dihydroxyvitamin solution once daily is equivalent to a total daily dose of 6-10 μg to about 300-500 μg 1,25-dihydroxyvitamin. 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).
Applicant argues:
The Office Action relies on Pitre for allegedly disclosing a composition comprising calcitriol that is preferably in a dosing spray bottle equipped with a 25 pl dosing valve. Pitre describes compositions comprising Vitamin D derivatives, at least one volatile silicone, and a nonvolatile oily phase in a physiologically acceptable medium for use in cosmetics and dermatology. Pitre fails to teach or suggest the use of a Vitamin D compound for the prevention of alopecia. Thus Pitre, even when combined with Jimenez, fails to teach or suggest that a total daily dose of about 10-100 µg of a Vitamin D compound by topical administration would result in safe and effective prevention of alopecia, as demonstrated by Applicant, for at least this reason. While claim 2 of Pitre recites a composition comprising between 0.0001 and 20% by weight of the active agent, Pitre fails to teach or suggest any total daily dose of a Vitamin D compound, much less the particular total daily dose range required by the present claims, i.e., a total daily dose of about 10-100 µg. For example, while Pitre discloses that "the spray device used consists of a bottle equipped with a 25 pl dosing valve", Pitre fails to disclose the total amount of a Vitamin D compound that is administered daily to a subject. Specifically, assuming that the composition recited in claim 2 has a weight similar to the weight of water, even at the highest recited concentration of 20% by weight, a 25 pl dose of the composition would contain only 5 µg of the active agent, much less than the total daily dose of 10-100 µg required by the present claims.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Applicants are reminded that it must be remembered that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and it is not that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, as set forth above, Jimenez ‘509 teaches a method of reducing chemotherapy-induced alopecia comprising topically administering to a patient undergoing chemotherapy a therapeutically effective amount of 1,25-dihydroxyvitamin D3. As set forth above, Pitre teaches a composition comprising calcitriol formulated in a spray composition for use in a metered spray bottle which is useful for treating alopecia of various origins. Thus, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize a metered spray unit to deliver composition taught by Jimenez topically to the scalp for treating alopecia induced by chemotherapeutic agents since the prior art teaches this as a method of administration for administering calcitriol for treating alopecia induced by chemotherapeutic agents.
Applicant argues:
The Office Action relies on Dr. Mercola and Sunshine Mist for allegedly teaching "a metered dose spray composition comprising vitamin D wherein the serving size is 6 sprays (approximately 0.78 mL)". Dr. Mercola is a web page describing a Vitamin D spray for oral administration. Sunshine Mist is a nutritional label for a Sunshine Mist Vitamin D "Spearmint Flavor Dietary Supplement". Like Pitre, Dr. Mercola and Sunshine Mist fail to teach or suggest the use of a Vitamin D compound for the prevention of alopecia. Furthermore, Dr. Mercola and Sunshine Mist fail to teach or suggest administering the disclosed Vitamin D spray topically to the scalp, as required by the present claims, much less the relatively high topical daily dose required by the claims as currently amended, i.e., a total daily dose of about 10-100 µg of a Vitamin D compound. Thus Dr. Mercola and Sunshine Mist, even when combined with Pitre and Jimenez, fail to teach or suggest that a total daily dose of about 10-100 µg of a Vitamin D compound by topical administration would result in safe and effective prevention of alopecia, as demonstrated by Applicant.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Applicants are reminded that it must be remembered that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and it is not that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, as set forth above, Jimenez ‘509 teaches a method of reducing chemotherapy-induced alopecia comprising topically administering to a patient undergoing chemotherapy a therapeutically effective amount of 1,25-dihydroxyvitamin D3 in dosage amounts that render the instantly claimed amounts obvious directly to the scalp. As set forth above, Pitre teaches a composition comprising calcitriol formulated in a spray composition for use in a metered spray bottle which is useful for treating alopecia of various origins and a spray bottle with a 25µl dosing valve. As set forth above, Dr. Mercola Premium Supplements Sunshine Mist™ Vitamin D Spray product label teaches serving size is 6 sprays (approximately 0.78 mL).As set forth above, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize a metered spray unit to deliver composition taught by Jimenez topically to the scalp for treating alopecia induced by chemotherapeutic agents since the prior art teaches this as a method of administration for administering calcitriol for treating alopecia induced by chemotherapeutic agents. As set forth above, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize the dispense dose, number of spray doses, and amount of dispenses (sprays) the container holds taught by Jimenez, Pitre and Dr. Mercola Premium Supplements as a starting point for optimizing the spray dispenser to deliver the optimum dose of the vitamin D derivative calcitriol for supplementing the subject without overdosing.
Jimenez, Pitre, Dr. Mercola, Sunshine Mist and Breastcancer.org
Applicant argues:
The Office Action relies on Breastcancer. org for allegedly treating early-stage breast cancer with Adriamycin and Cytoxan. Breastcancer.org fails to mention a Vitamin D compound. Thus, like Pitre, Dr. Mercola and Sunshine Mist, Breastcancer. org fails to teach or suggest the use of a Vitamin D compound for the prevention of alopecia, much less the relatively high topical daily dose of a Vitamin D compound required by the claims as currently amended, i.e., a total daily dose of about 10-100 µg of a Vitamin D compound. Thus Dr. Mercola and Sunshine Mist, even when combined with Pitre and Jimenez, fail to teach or suggest that a total daily dose of about 10-100 µg of a Vitamin D compound by topical administration would result in safe and effective prevention of alopecia, as demonstrated by Applicant.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Applicants are reminded that it must be remembered that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and it is not that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
As set forth above, Jimenez ‘509, Pitre, and Dr. Mercola Premium Supplements Sunshine Mist™ Vitamin D Spray product label teach a method of reducing chemotherapy-induced alopecia comprising topically administering to a patient undergoing chemotherapy a therapeutically effective amount of 1,25-dihydroxyvitamin D3 in dosage amounts that render the instantly claimed amounts obvious directly to the scalp. As set forth above, Jimenez teaches pretreatment with vitamin D3 provided protection from chemotherapy induced alopecia from Adriamycin and Cytoxan combination (Table II). As set forth above, Breastcancer.org teaches a study suggests that treating early-stage breast cancer with two common chemotherapy medicines followed by a third (doctors call this a sequential approach) has some advantages compared to giving two or three chemotherapy medicines at the same time; the women were treated with two or three common chemotherapy medicines which included Adriamycin and Cytoxan. As set forth above, it would have been obvious to one of ordinary skill in the art to utilize the method of reducing chemotherapy-induced alopecia suggested by Jimenez ‘509 and Pitre in a subject having breast cancer treated with Adriamycin and Cytoxan since the prior art teaches pretreatment with vitamin D3 provided protection from chemotherapy induced alopecia from Adriamycin and Cytoxan combination and Adriamycin and Cytoxan combination is a common chemotherapy for breast cancer, resulting in the practice of the method of the instant claims with a reasonable expectation of success.
The '917 application, Pitre, Dr. Mercola and Sunshine Mist
Applicant argues:
While the '917 application fully supports and enables all of the embodiments disclosed and claimed therein, the '917 application does not disclose the particular administration method required by the present claims, i.e., topically administering a pharmaceutical composition comprising therapeutically effective amount of a vitamin D compound to the scalp of the subject using a metered spray unit wherein the pharmaceutical composition comprises the vitamin D compound at a concentration of 5-20 µg/mL, and the pharmaceutical composition is administered in an about 1.0 mL dose and at a total daily dose of about 10-100 µg of the vitamin D compound. Accordingly, the safety and efficacy of this particular administration method demonstrated by Applicant would not have been expected from the teachings of the '917 application. Pitre describes compositions comprising Vitamin D derivatives, at least one volatile silicone, and a nonvolatile oily phase in a physiologically acceptable medium for use in cosmetics and dermatology. Pitre fails to teach or suggest the use of a Vitamin D compound for the prevention of alopecia. Thus Pitre, even when combined with Jimenez, fails to teach or suggest that a total daily dose of about 10-100 µg of a Vitamin D compound by topical administration would result in safe and effective prevention of alopecia, as demonstrated by Applicant, for at least this reason. Furthermore, while claim 2 of Pitre recites a composition comprising between 0.0001 and 20% by weight of the active agent, Pitre fails to teach or suggest any total daily dose of a Vitamin D compound, much less the particular total daily dose range required by the present claims, i.e., a total daily dose of about 10-100 µg. For example, while Pitre discloses that "the spray device used consists of a bottle equipped with a 25 µl dosing valve", Pitre fails to disclose the total amount of a Vitamin D compound that is administered daily to a subject. Specifically, assuming that the composition recited in claim 2 has a weight similar to the weight of water, even at the highest recited concentration of 20% by weight, a 25 pl dose of the composition would contain only 5 g of the active agent, much less than the total daily dose of 10-100 µg required by the present claims.
The Office Action relies on Dr. Mercola and Sunshine Mist for allegedly teaching "a metered dose spray composition comprising vitamin D wherein the serving size is 6 sprays (approximately 0.78 mL)". Dr. Mercola is a web page describing a Vitamin D spray for oral administration. Sunshine Mist is a nutritional label for a Sunshine Mist Vitamin D "Spearmint Flavor Dietary Supplement". Like Pitre, Dr. Mercola and Sunshine Mist fail to teach or suggest the use of a Vitamin D compound for the prevention of alopecia. Furthermore, Dr. Mercola and Sunshine Mist fail to teach or suggest administering the disclosed Vitamin D spray topically to the scalp, as required by the present claims, much less the relatively high topical daily dose required by the claims as currently amended, i.e., a total daily dose of about 10-100 µg of a Vitamin D compound. Thus Dr. Mercola and Sunshine Mist, even when combined with Pitre and Jimenez, fail to teach or suggest that a total daily dose of about 10-100 µg of a Vitamin D compound by topical administration would result in safe and effective prevention of alopecia, as demonstrated by Applicant.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Applicants are reminded that it must be remembered that the references are relied upon in combination and are not meant to be considered separately as in a vacuum. It is the combination of all of the cited and relied upon references, which make up the state of the art with regard to the claimed invention. As set forth above, Jimenez ‘917 teaches a topical solution for inhibiting alopecia induced by chemotherapeutic agents comprising 1,25-dihydroxyvitamin D3, propylene glycol and ethyl alcohol wherein 1,25-dihydroxyvitamin D3 is administered in a concentration of 0.1, 0.2, 0.5, 1.0, 2, 3, 5, 10, 20, 30, 50, 75, 100, 150, 200, or 400 μg/mL at a dose volume of 2.1 mL. As set forth above, Pitre teaches a composition comprising calcitriol formulated in a spray composition for use in a metered spray bottle equipped with a 25µl dosing valve. As set forth above, Dr. Mercola Premium Supplements teaches a metered dose spray composition comprising vitamin D wherein the serving size is 6 sprays (approximately 0.78 mL) in a container containing about 32 servings. As set forth above, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize the dispense dose, number of spray doses, and amount of dispenses (sprays) the container holds taught by Dr. Mercola Premium Supplements as a starting point for optimizing the spray dispenser to deliver the optimum dose of the vitamin D derivative calcitriol for supplementing the subject without overdosing.
Maintained Objections and/or Rejections
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agre