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 .
DETAILED ACTION
Claims 33-41 are pending and under examination. Claims 1-32 are cancelled.
The rejection of claims 33-39 under 35 U.S.C. 112(b) is withdrawn in view of the amendment.
Response to Arguments
Applicant's arguments filed 9/30/2025 have been fully considered but they are not persuasive.
Applicant argues against the written description rejection of claims 33-41 under 35 U.S.C. 112(a) on the grounds that the active agent PLAP is discussed by Dr. Kiss in detail at paragraphs [0037]-[0042] of the published application, explaining the structure, sources and activities of PLAP as appropriate for use in the context of the claimed method (Arguments, page 6, paragraph 3).
In response, the specification only discloses a single species of active derivative of PLAP, which is replacement of the glycosylphosphatidylinositol anchoring sequence of PLAP with the FLAG octapeptide, in order to simplify the recovery and purification of rPLAP ((page 16, Example 1, paragraph 2). This single active derivative is not representative of the claimed genus. As explained within the written description rejection, although the structure of human placental alkaline phosphatase was known in the art, Le Du teaches that the enzyme is a dimer and that the binding of the substrate to one active site affects the second binding site (Le Du et al., page 9160, bottom paragraph on left column through first paragraph on right column). In other words, the activity of the enzyme depends not only on the active site but also the dimerization of human placental alkaline phosphatase monomers. Amino acid modifications outside of the active site would have had unpredictable effects on the conformation of the monomers and their ability to dimerize. The prior art only teaches active derivatives of placental alkaline phosphatase that are minimal terminal truncations of the enzyme (e.g. Heino et al., page 86, right column, “Construction of the P. pastoris Strain Expressing PLAP,” first paragraph). However, the scope of the claimed invention is not limited to such modifications.
Applicant argues against the rejection of claims 33-41 under 35 U.S.C. 103 on the grounds of unexpected results. Applicant points to [0028] and [0070] of the specification: at first sight, using PLAP for treating acne may sound counterintuitive because a major goal in acne treatment is to initially reduce proliferation of keratinocytes, while PLAP was shown to enhance proliferation of keratinocytes. However depending on the concentration of extracellular ATP, PLAP and rPLAP will exert two different effects on skin cell proliferation. In the presence of ATP in the extracellular space (like in inflamed tissues), PLAP and rPLAP will inhibit proliferation of skin cells, while in the absence of ATP in the extracellular space (in the regenerative phase) PLAP and rPLAP will stimulate proliferation of skin cells thereby helping to restore the damaged skin (Arguments, page 8, paragraphs 1-2).
In response, the prior art of Kiss teaches that inflammation is associated with scarring during healing ([0006]), thus it would have been obvious to the person of ordinary skill in the art that reducing inflammation would have promoted scar-free healing. In addition, Kiss teaches that PLAP controls inflammation and skin infection ([0002] and [0078]). Therefore, the fact that administering PLAP to acne lesions promotes scar-free healing is not unexpected. The proposed mechanism of action for PLAP is not an unexpected result.
Applicant argues further against the rejection of claims 33-41 under 35 U.S.C. 103 on the grounds that Kiss uses a combination of lactoferrin and PLAP to achieve promotion of survival and proliferation of skin cells (Arguments, bottom paragraph on page 9).
In response, claim 33 recites “by,” which is a transitional phrase that must be interpreted in light of the specification to determine whether open or closed claim language is intended (MPEP 2111.03(IV). Here, the specification discloses “In some embodiments, the PLAP cream may include one or more well tested additives or enhancers from a list offered by pharmaceutical companies including preservatives, biologically active compounds with positive effects on the recovery of normal skin texture, buffers, moisture-control compounds, or antibiotics (specification, page 14, paragraph 3). Here, lactoferrin is a biologically active compound that stimulates cell proliferation (Kiss [0012]). In addition, claim 33 recites administering PLAP dispersed in a suitable carrier, which is exemplified in the specification as Vaselinum (page 13, B. Methods of Use, Local Treatment of Acne with PLAP Cream, paragraph 1). Vaselinum (Latin name for petroleum jelly) itself is beneficial for scar-free healing because it keeps wounds moist (AAD, page 2, number 2). Therefore, claims 33-41 are interpreted as open (i.e. the method does not exclude administering additional components such as lactoferrin).
Applicant argues that Kiss is directed to the treatment of a condition that is different from the present described condition using methods and materials that are different from the methods and materials required in the present method claims as amended (Arguments, paragraph 2 on page 10). Applicant argues the skilled artisan would have no indication from the teachings of these references even when considered in combination that topical administration of human placental alkaline phosphatase or one of its active derivatives to an area of acne vulgaris infected by Propionibacterium acnes bacteria could achieve the surprising result of preventing formation of scar tissue for scar-free healing of the area (Arguments, bottom paragraph on page 14).
In response, Kiss teaches that the composition comprising PLAP when administered reduces inflammation and microbial infection in the skin (Abstract). Kiss teaches that the administration of placental alkaline phosphatase promotes wound healing and controls inflammation and skin infection ([0002] and [0078]). Both inflammation and infection are known to occur in an area of acne vulgaris infected by Propionibacterium acnes. Dreno teaches that inflammation is associated with all acne lesions (Abstract) and infection is also necessarily present due to the presence of Propionibacterium acnes. Furthermore, Kiss teaches that inflammation is associated with scarring during healing ([0006]). Therefore, topically administering PLAP to an area of acne vulgaris would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention and the result of scar-free healing is not unexpected.
With respect to the nonstatutory double patenting rejections of record, no new arguments are presented that are not already addressed above.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 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.
Claim 40 is 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 40, as amended, recites topical application for a time sufficient to heal the acne lesion by about 80-85% without visible scar tissue. There are at least three different reasonable interpretations of this limitation, rendering the claim indefinite. In one interpretation, the percentage refers to the completeness of healing (100% being completely healed). In a second interpretation, 80-85% refers to the area of acne vulgaris (80-85% of the area is healed). In a third interpretation, 80-85% refers to the area without scar tissue (i.e. 80-85% of the area of acne vulgaris is without visible scar tissue).
In addition, claim 40 recites the limitation "the acne lesion" in line 3. There is insufficient antecedent basis for this limitation in the claim because an area of acne vulgaris does not require the presence of a lesion.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(Maintained rejection for claims 33-40 and new rejection necessitated by amendment for claim 41) Claims 33-41 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 33 recites “A method for topically treating acne vulgaris by topically administering human placental alkaline phosphatase or one of its active derivatives dispersed in a suitable carrier to an area of acne vulgaris infected by Propionibacterium acnes bacteria to combine with extracellular ATP derived from damaged cells of the area and/or from the Propionibacterium acnes bacteria in a therapeutically effective amount to prevent formation of scar tissue for scar-free healing of the area.”
The specification defines “active derivative of PLAP” as “a sequence specifically derived from PLAP produced by a recombinant, enzymatic, or chemical method that can promote healing of acne” (page 12, A. The active agent, paragraph 1). The specification also states that “The recombinant active derivative (rPLAP) has catalytic alkaline phosphatase activity and contains at least 80% of the sequence of the full length rPLAP” (page 12, A. The active agent, paragraph 1). However, claim 33 recites “administering human placental alkaline phosphatase or one of its active derivatives” and does not recite rPLAP or a recombinant active derivative. Thus, the broadest reasonable interpretation of “active derivative” in claim 33 is given by the definition “a sequence specifically derived from PLAP produced by a recombinant, enzymatic, or chemical method that can promote healing of acne.” Therefore, the scope of “active derivative” encompasses any number of amino acid substitutions or modifications so long as the enzyme retains its activity.
The specification discloses a single species of active derivative of human placental alkaline phosphatase: “To simplify the recovery and purification of rPLAP, the glycosylphosphatidylinositol anchoring sequence of PLAP was replaced by the FLAG octapeptide, and rPLAP was expressed as secreted, epitope-tagged, enzyme” (page 16, Example 1, paragraph 2).
Heino et al. (Protein expression and purification 12.1 (1998): 85-92; cited in the Final Action mailed on 10/24/2023) teaches expressing the soluble form of human placental alkaline phosphatase in Pichia pastoris (Abstract). Heino teaches that the hydrophobic C-terminal portion beyond the Asp-484 was omitted from the placental alkaline phosphatase fragment (page 86, right column, “Construction of the P. pastoris Strain Expressing PLAP,” first paragraph). Heino teaches that deletion of the last 29 amino acids of the sequence, which are a signal for phosphoinositolglycan (“PI-G”) attachment, makes the enzyme soluble (page 86, right column, “Construction of the P. pastoris Strain Expressing PLAP,” first paragraph). Heino’s recombinant human placental alkaline phosphatase enzyme retains its catalytic activity (page 89, left column, middle paragraph). Since Heino’s recombinant enzyme is a catalytically-active, truncated form of human placental alkaline phosphatase enzyme, Heino’s enzyme is an active derivative.
Le Du et al. (Journal of Biological Chemistry 276.12 (2001): 9158-9165) teaches the crystal structure of alkaline phosphatase from human placenta (Title). Le Du teaches that the overall structure of PLAP is a dimer, wherein each monomer contains 479 residues (page 9160, left column, Results and Discussion, Overall Structure). Le Du teaches that the stability and catalytic properties of each monomer are controlled by the conformation of the second alkaline phosphatase subunit: “the principle of allostery implies that the binding of the substrate in one active site will affect the second binding site” (page 9160, bottom paragraph on left column through first paragraph on right column). Therefore, not only the amino acid residues in the catalytic site are important for the activity of the enzyme but also the amino acid residues that control the dimerization of the alkaline phosphatase subunits.
Although the structure of human placental alkaline phosphatase was known in the art, given Le Du’s teaching that the activity of the enzyme depends not only on the active site but also the dimerization of human placental alkaline phosphatase monomers, the person of ordinary skill in the art would have been unable to predict the effect of amino acid modifications on the catalytic activity of the enzyme. Amino acid modifications outside of the active site would have had unpredictable effects on the conformation of the monomers and their ability to dimerize. The prior art only teaches active derivatives of placental alkaline phosphatase that are minimal terminal truncations of the enzyme. However, the scope of the claim is not limited to such modifications.
Based on the above analysis, the person of ordinary skill in the art would not have recognized that the inventors were in possession of the claimed genus of active derivatives of human placental alkaline phosphatase.
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.
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.
Claims 33-39 remain rejected under 35 U.S.C. 103 as being unpatentable over Kiss et al. (US 2007/0059300 A1; cited in the Non-Final Action mailed on 5/9/2023) in view of Dreno et al. (Journal of the European Academy of Dermatology and Venereology 29 (2015): 3-11; cited in the Non-Final Action mailed on 5/9/2023) and as evidenced by Cleveland Clinic (cited in the Final Action mailed on 10/24/2023) and by Mempin et al. (BMC microbiology 13 (2013): 1-13; cited in the Final Action mailed on 9/4/2024).
Kiss teaches a method for stimulating proliferation and inhibiting the death of skin cells in wounded skin (Abstract). The method includes a step of topically administering to an area of host skin a composition comprising alkaline phosphatase such as placental alkaline phosphatase (Abstract). Kiss teaches that the composition when administered reduces inflammation and microbial infection in the skin (Abstract). Kiss teaches that the administration of placental alkaline phosphatase promotes wound healing and controls inflammation and skin infection ([0002] and [0078]). Kiss teaches administering a therapeutically effective amount of placental alkaline phosphatase in a physiologically compatible carrier ([0076]). Kiss teaches that the placental alkaline phosphatase is human (see [0038]).
Kiss’s composition comprises anti-acne agents ([0096]).
Kiss teaches that inflammation is associated with scarring during healing ([0006]). Kiss teaches that a recent trend among dermatologists is to attempt to reduce the inflammation phase to avoid excessive scarring during healing ([0006]).
Kiss does not teach topically administering human placental alkaline phosphatase to an area of acne vulgaris infected by Propionibacterium acnes bacteria. Kiss does not teach that human placental alkaline phosphatase combines with extracellular ATP derived from damaged cells or from Propionibacterium acnes.
Dreno teaches that the pathogenesis of acne (synonym for acne vulgaris, as evidenced by Cleveland Clinic, last line on page 2) involves multiple factors, including an inflammatory immune response to the bacterium Propionibacterium acnes (Abstract). Dreno teaches that inflammation is associated with all acne lesions (Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Kiss by topically administering human placental alkaline phosphatase to an area of acne vulgaris infected by Propionibacterium acnes. One of ordinary skill in the art would have been motivated by the teaching of Dreno, which suggested that inflammation was present in all acne lesions, and the teaching of Kiss that human placental alkaline phosphatase reduced inflammation in skin wounds. Furthermore, one of ordinary skill in the art would have recognized based on the teaching of Dreno that the pathogenesis of acne involved the body’s response to Propionibacterium acnes, which is a bacterium. Therefore, it would have been further obvious that a reduction in Propionibacterium acnes would have benefited the healing of an area of acne vulgaris. Thus, the topical administration of placental alkaline phosphatase to an area of acne vulgaris infected by Propionibacterium acnes would have been obvious to one of ordinary skill in the art because placental alkaline phosphatase was already known to both reduce inflammation and microbial infection. Since Kiss teaches that reducing inflammation reduces scarring, then Kiss’s composition, which reduces inflammation, necessarily prevents the formation of scar tissue.
Bacteria produce extracellular ATP during growth, as evidenced by Mempin (Abstract Results and Abstract Conclusion). Therefore, extracellular ATP is necessarily present in an area of acne vulgaris infected by Propionibacterium acnes due to the growth of Propionibacterium acnes. Thus, topically administering human placental alkaline phosphatase to an area of acne vulgaris infected by Propionibacterium acnes necessarily combines extracellular ATP with human placental alkaline phosphatase.
Pertaining to claims 37-39, Kiss teaches topically administering creams of placental alkaline phosphatase comprising 1.2 mg of placental alkaline phosphatase in 1-g vaselinum cholesterinatum to mice grafted with human skin and subsequently burned ([0173]), 1.2 mg of placental alkaline phosphatase in 1-g vaselinum cholesterinatum overlaps with 0.51 to 2.0 mg of placental alkaline phosphatase in one gram carrier.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to topically administer 1.2 mg of placental alkaline phosphatase in 1-g vaselinum cholesterinatum for the treatment of acne since inflammation would have been common to both burns and acne. One of ordinary skill in the art would have been motivated by the results of Kiss, which suggested a therapeutically effective amount for the treatment of burns in an animal model.
It would have been further obvious to routinely optimize the method to decrease or increase the amount of the active ingredient (human placental alkaline phosphatase), for the treatment of light or severe acne lesions, respectively. One of ordinary skill in the art would have expected that increasing the amount of human placental alkaline phosphatase would have been necessary for more severe cases of acne and decreasing the amount of human placental alkaline phosphatase would have been necessary for less severe (light) cases of acne because more severe acne would have been expected to exhibit more inflammation and thus would have required more of the active ingredient.
Pertaining to claim 34, Kiss teaches administering 1.2 mg of placental alkaline phosphatase in 1-g vaselinum cholesterinatum ([0172]).
Pertaining to claim 35, Kiss teaches that the carrier may be vaselinum flavum or vaselinum album ([0088]).
Pertaining to claim 36, Kiss teaches that the composition may comprise an active derivative of human placental alkaline phosphatase produced by recombinant methods ([0068]). Kiss’s active derivative necessarily reproduces all effects of full length human placental alkaline phosphatase because they are biologically functional equivalents ([0064]).
Claims 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Kiss in view of Dreno as evidenced by Cleveland Clinic and by Mempin, as applied to claims 33-39 above, further in view of Mayo Clinic (cited in the Non-Final Action mailed on 5/9/2023).
Claim 40 is interpreted as requiring that the area of acne vulgaris heals by 80-85% relative to complete healing (100%).
See discussion of Kiss and Dreno above, which is incorporated into this rejection as well.
Regarding claim 40, Kiss does not teach daily topical application of human placental alkaline phosphtase for a time sufficient to heal the acne lesion by about 80-85% without visible scar tissue.
Regarding claim 41, Kiss does not teach daily topical application of human placental alkaline phosphatase for about three weeks.
However, daily topical application for weeks to months is a standard of care for other topical acne treatments such as benzoyl peroxide cream, as taught by Mayo Clinic (see page 1, paragraph 1 and page 3, For acne: For topical dosage forms (cleansing lotion, cream, or gel)).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to topically administer human placental alkaline phosphatase per the method of Kiss and Dreno daily. One of ordinary skill in the art would have been motivated by the teaching of Mayo Clinic, which suggests a daily regimen for acne treatment. Furthermore, it would have been obvious to optimize by routine experimentation the duration of the treatment such that the acne lesion was mostly healed (e.g. 80-85%). The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the duration of treatment.
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 agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/ patents/apply/applying-online/eterminal-disclaimer
The following rejections are necessitated by the amendment.
Claims 33-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 7,011,965 (hereafter ‘965) in view of Kiss et al. (US 2007/0059300 A1; cited in the Non-Final Action mailed on 5/9/2023) and Dreno et al. (Journal of the European Academy of Dermatology and Venereology 29 (2015): 3-11; cited in the Non-Final Action mailed on 5/9/2023) and as evidenced by Cleveland Clinic (cited in the Final Action mailed on 10/24/2023) and by Mempin et al. (BMC microbiology 13 (2013): 1-13; cited in the Final Action mailed on 9/4/2024).
Claim 1 of ‘965 recites “A composition for skin wound healing in a patient comprising placental alkaline phosphatase in an amount effective for stimulating proliferation of fibroblasts and a gel-forming material, wherein said composition is formulated for topical delivery.” Claim 7 of ‘965 further limits the gel-forming material in the composition of claim 1.
Claims 1 and 7 of ‘965 do not recite topically administering human placental alkaline phosphatase to an area of acne vulgaris infected by Propionibacterium acnes bacteria. Claims 1 and 7 of ‘965 do not recite that human placental alkaline phosphatase combines with extracellular ATP derived from damaged cells or from Propionibacterium acnes.
Kiss teaches a method for stimulating proliferation and inhibiting the death of skin cells in wounded skin (Abstract). The method includes a step of topically administering to an area of host skin a composition comprising alkaline phosphatase such as placental alkaline phosphatase (Abstract). Kiss teaches that the composition when administered reduces inflammation and microbial infection in the skin (Abstract). Kiss teaches that the administration of placental alkaline phosphatase promotes wound healing and controls inflammation and skin infection ([0002] and [0078]). Kiss teaches administering a therapeutically effective amount of placental alkaline phosphatase in a physiologically compatible carrier ([0076]). Kiss teaches that the placental alkaline phosphatase is human (see [0038]).
Kiss’s composition comprises anti-acne agents ([0096]).
Kiss teaches that inflammation is associated with scarring during healing ([0006]). Kiss teaches that a recent trend among dermatologists it to attempt to reduce the inflammation phase to avoid excessive scarring during healing ([0006]).
Dreno teaches that the pathogenesis of acne (synonym for acne vulgaris, as evidenced by Cleveland Clinic, last line on page 2) involves multiple factors, including an inflammatory immune response to the bacterium Propionibacterium acnes (Abstract). Dreno teaches that inflammation is associated with all acne lesions (Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the composition of claim 1 or 7 of ‘965 with the composition of Kiss comprising placental alkaline phosphatase. Such a combination would have constituted combining equivalents known in the art for the same purpose (promoting skin wound healing). It would have further obvious to topically administer the combined composition of claim 1 or 7 of ‘965 to an area of acne vulgaris infected by Propionibacterium acnes in order to prevent scar tissue formation. One of ordinary skill in the art would have been motivated by the teaching of Dreno, which suggested that inflammation was present in all acne lesions and the teaching of Kiss that placental alkaline phosphatase reduced inflammation in skin wounds. Furthermore, one of ordinary skill in the art would have recognized based on the teaching of Dreno that the pathogenesis of acne involved the body’s response to Propionibacterium acnes, which is a bacterium. Therefore, it would have been further obvious that a reduction in Propionibacterium acnes would have benefited the healing of an area of acne vulgaris infected by Propionibacterium acnes. Thus, the topical administration of placental alkaline phosphatase to an area of acne vulgaris infected by Propionibacterium acnes would have been obvious to one of ordinary skill in the art because placental alkaline phosphatase was already known to both reduce inflammation and microbial infection. Since Kiss taught that reducing inflammation would have reduced scarring, then the combination of the composition of ‘965 with Kiss’s composition, which reduced inflammation, would have necessarily promoted scar-free healing.
Bacteria produce extracellular ATP during growth, as evidenced by Mempin (Abstract Results and Abstract Conclusion). Therefore, extracellular ATP is necessarily present in an area of acne vulgaris infected by Propionibacterium acnes due to the growth of Propionibacterium acnes. Thus, topically administering human placental alkaline phosphatase to an area of acne vulgaris infected by Propionibacterium acnes necessarily combines extracellular ATP with human placental alkaline phosphatase.
Pertaining to claims 37-39, Kiss teaches topically administering creams of placental alkaline phosphatase comprising 1.2 mg of placental alkaline phosphatase in 1-g vaselinum cholesterinatum to mice grafted with human skin and subsequently burned ([0173]), 1.2 mg of placental alkaline phosphatase in 1-g vaselinum cholesterinatum overlaps with 0.51 to 2.0 mg of placental alkaline phosphatase in one gram carrier.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to adjust the concentration of placental alkaline phosphatase in the combined composition of ‘965 and Kiss in order to topically administer 1.2 mg of placental alkaline phosphatase in 1-g vaselinum cholesterinatum for the treatment of an area of acne vulgaris infected by Propionibacterium acnes. One of ordinary skill in the art would have recognized that inflammation would have been common to both burns and acne vulgaris, hence one of ordinary skill in the art would have been motivated to use a similar concentration to treat both conditions.
It also would have been obvious to routinely optimize the method to decrease or increase the amount of the active ingredient (placental alkaline phosphatase), for the treatment of light or severe acne, respectively,. One of ordinary skill in the art would have expected that increasing the amount of placental alkaline phosphatase would have been necessary for more severe acne and decreasing the amount of placental alkaline phosphatase would have been necessary for less severe (light) acne because more severe lesions would have been expected to exhibit more inflammation and thus would have required more of the active ingredient.
Pertaining to claim 34, Kiss teaches administering 1.2 mg of placental alkaline phosphatase in 1-g vaselinum cholesterinatum ([0172]). Thus, the combination of the composition of ‘965 and Kiss would have comprised vaselinum cholesterinatum as the carrier.
Pertaining to claim 35, Kiss teaches that the carrier may be vaselinum flavum or vaselinum album ([0088]). Thus, the combination of the composition of ‘965 and Kiss would have comprised vaselinum flavum or vaselinum album as the carrier.
Regarding claim 36, Kiss teaches that the composition may comprise an active derivative of human placental alkaline phosphatase produced by recombinant methods ([0068]). Kiss’s active derivative necessarily reproduces all effects of full length human placental alkaline phosphatase because they are biologically functional equivalents ([0064]).
Claims 40-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of U.S. Patent No. 7,011,965 (hereafter ‘965) in view of Kiss and Dreno as evidenced by Cleveland Clinic and Mempin, as applied to claims 33-39 above, further in view of Mayo Clinic (cited in the Non-Final Action mailed on 5/9/2023).
See discussion of claims 1 and 7 of ‘965, Kiss, and Dreno above, which is incorporated into this rejection.
Regarding claim 40, claims 1 and 7 of ‘965, Kiss, and Dreno do not teach daily topical application of human placental alkaline phosphatase for a time sufficient to heal the acne lesion by about 80-85% without visible scar tissue.
Regarding claim 41, claims 1 and 7 of ‘965, Kiss, and Dreno do not teach daily topical application of placental alkaline phosphatase for about three weeks.
However, daily topical application for a period of time on the order of weeks to months is a standard of care for other topical acne treatments such as benzoyl peroxide cream, as taught by Mayo Clinic (see page 1, paragraph 1 and page 3, For acne: For topical dosage forms (cleansing lotion, cream, or gel)).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to topically administer human placental alkaline phosphatase per the method of claims 1 and 7 of ‘965, Kiss, and Dreno daily. One of ordinary skill would have been motivated by the teaching of Mayo Clinic, which suggested a daily regimen for acne treatment. Furthermore, it would have been obvious to optimize by routine experimentation the duration of the treatment such that the acne lesion was mostly healed (e.g. 80-85%). The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the duration of treatment.
Claims 33-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20 and 24 of U.S. Patent No. 7,374,754 (hereafter ‘754) in view of Kiss and Dreno and as evidenced by Cleveland Clinic and by Mempin.
Claim 20 of ‘754 recites “A method for stimulating proliferation of cells in an epidermis and a dermis of transplanted skin, comprising the step of topically administering to an area of the transplanted skin a composition comprising Vaselinum flavum or Vaselinum album, and human placental alkaline phosphatase.”
Claim 24 of ‘754 recites “A composition for topical application comprising Vaselinum flavum, Vaselinum album or Vaselinum cholesterinatum, and an amount of human placental alkaline phosphatase effective to stimulate proliferation of cells in an epidermis and a dermis of mammalian skin.”
Claims 20 and 24 of ‘754 do not recite topically administering human placental alkaline phosphatase to an area of acne vulgaris infected by Propionibacterium acnes bacteria. Claims 20 and 24 of ‘754 do not recite that human placental alkaline phosphatase combines with extracellular ATP derived from damaged cells or from Propionibacterium acnes.
Kiss teaches a method for stimulating proliferation and inhibiting the death of skin cells in wounded skin (Abstract). The method includes a step of topically administering to an area of host skin a composition comprising alkaline phosphatase such as placental alkaline phosphatase (Abstract). Kiss teaches that the composition when administered reduces inflammation and microbial infection in the skin (Abstract). Kiss teaches that the administration of placental alkaline phosphatase promotes wound healing and controls inflammation and skin infection ([0002] and [0078]). Kiss teaches administering a therapeutically effective amount of placental alkaline phosphatase in a physiologically compatible carrier ([0076]). Kiss teaches that the placental alkaline phosphatase is human (see [0038]).
Kiss’s composition comprises anti-acne agents ([0096]).
Kiss teaches that inflammation is associated with scarring during healing ([0006]). Kiss teaches that a recent trend among dermatologists it to attempt to reduce the inflammation phase to avoid excessive scarring during healing ([0006]).
Dreno teaches that the pathogenesis of acne (synonym for acne vulgaris, as evidenced by Cleveland Clinic, last line on page 2) involves multiple factors, including an inflammatory immune response to the bacterium Propionibacterium acnes (Abstract). Dreno teaches that inflammation is associated with all acne lesions (Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the composition of claim 24 of ‘754 with the composition of Kiss comprising placental alkaline phosphatase and topically administer the compositions to an area of acne vulgaris. Both compositions were art-recognized equivalents for the same purpose (promoting skin healing or stimulating proliferation of cells). One of ordinary skill in the art would have been motivated by the teaching of Kiss, which suggested that human placental alkaline phosphatase would have been beneficial to reduce inflammation and microbial infection, as well as Dreno’s teaching that inflammation had been demonstrated in all acne vulgaris lesions. Alternatively, it would have been obvious to modify the method of claim 20 of ‘754 to administer human placental alkaline phosphatase to an area of acne vulgaris infected by Propionibacterium acnes based on the teachings of Kiss and Dreno. Since Kiss teaches that scarring is associated with inflammation, then reducing inflammation during healing also necessarily promotes scar-free healing.
Bacteria produce extracellular ATP during growth, as evidenced by Mempin (Abstract Results and Abstract Conclusion). Therefore, extracellular ATP is necessarily present in an area of acne vulgaris infected by Propionibacterium acnes due to the growth of Propionibacterium acnes. Thus, topically administering human placental alkaline phosphatase to an area of acne vulgaris infected by Propionibacterium acnes necessarily combines extracellular ATP with human placental alkaline phosphatase.
Pertaining to claims 37-39, Kiss teaches topically administering creams of placental alkaline phosphatase comprising 1.2 mg of placental alkaline phosphatase in 1-g vaselinum cholesterinatum to mice grafted with human skin and subsequently burned ([0173]), 1.2 mg of placental alkaline phosphatase in 1-g vaselinum cholesterinatum overlaps with 0.51 to 2.0 mg of placental alkaline phosphatase in one gram carrier.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to adjust the concentration of placental alkaline phosphatase in the method of claims 20 and 24 of ‘754 modified by Kiss and Dreno in order to topically administer 1.2 mg of placental alkaline phosphatase in 1-g vaselinum cholesterinatum for the treatment of acne since inflammation would have been common to both burns and acne. One of ordinary skill would have been motivated by the results of Kiss, which suggested a therapeutically effective amount for the treatment of burns in an animal model.
It also would have been obvious to routinely optimize the method to decrease or increase the amount of the active ingredient (placental alkaline phosphatase), for the treatment of light or severe acne, respectively. One of ordinary skill in the art would have expected that increasing the amount of placental alkaline phosphatase would have been necessary for more severe lesions and decreasing the amount of placental alkaline phosphatase would have been necessary for less severe (light) lesions because more severe lesions would have been expected to exhibit more inflammation and thus would have required more of the active ingredient.
Pertaining to claims 34, claim 24 of ‘754 recite that the composition comprises human placental alkaline phosphatase and vaselinum cholesterinatum. Therefore, it would have been obvious to use vaselinum cholesterinatum as the carrier in the method of claims 20 and 24 of ‘754 modified by Kiss and Dreno.
Pertaining to claim 35, claims 20 and 24 of ‘754 recite compositions of human placental alkaline phosphatase with vaselinum flavum or vaselinum album as the carrier. Therefore, it would have been obvious to use vaselinum flavum or vaselinum album as the suitable carrier in the method of claims 20 and 24 of ‘754 modified by Kiss and Dreno.
Pertaining to claim 36, Kiss teaches that the composition may comprise an active derivative of human placental alkaline phosphatase produced by recombinant methods ([0068]). Kiss’s active derivative necessarily reproduces all effects of full length human placental alkaline phosphatase because they are biologically functional equivalents ([0064]). Therefore, it would have been obvious to use an active derivative of human placental alkaline phosphatase in the method of claims 20 and 24 of ‘754 modified by Kiss and Dreno.
Claims 40-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 20 and 24 of U.S. Patent No. 7,374,754 (hereafter ‘754) in view of Kiss and Dreno and as evidenced by Cleveland Clinic and by Mempin, as applied to claims 33-39 above, further in view of Mayo Clinic (cited in the Non-Final Action mailed on 5/9/2023).
See discussion of claims 20 and 24 of ‘754, Kiss, and Dreno above, which is incorporated into this rejection.
Regarding claim 40, claims 20 and 24 of ‘754 do not recite and Kiss and Dreno do not teach daily topical application of human placental alkaline phosphatase for a time sufficient to heal the acne lesion by about 80-85% without visible scar tissue.
Regarding claim 41, claims 20 and 24 of ‘754 do not recite and Kiss and Dreno do not teach daily topical application of human placental alkaline phosphatase for about three weeks.
However, daily topical application for a period of time on the order of weeks to months is a standard of care for other topical acne treatments such as benzoyl peroxide cream, as taught by Mayo Clinic (see page 1, paragraph 1 and page 3, For acne: For topical dosage forms (cleansing lotion, cream, or gel)).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to topically administer human placental alkaline phosphatase per the method of claims 20 or 24 of ‘754, Kiss, and Dreno daily. One of ordinary skill would have been motivated by the teaching of Mayo Clinic, which suggested a daily regimen for acne treatment. Furthermore, it would have been obvious to optimize by routine experimentation the duration of the treatment such that the acne lesion was mostly healed (e.g. 80-85%). The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the duration of treatment.
Claims 33-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-13, 15, and 18 of U.S. Patent No. 7,312,198 (hereafter ‘198) in view of Kiss and Dreno and as evidenced by Cleveland Clinic and by Mempin.
Claim 1 of ‘198 recites “A method for stimulating proliferation and promoting survival of cells in the epidermis and dermis of wounded or non-wounded mammalian skin, comprising the step of topically administering to skin a composition comprising therapeutically effective amounts of at least two active proteins, selected from […] alkaline phosphatase […].”
Claim 11 of ‘198 recites “The method of claim 1, wherein the skin is transplanted skin and the composition is administered to an area of the transplanted skin.” Claim 12 of ‘198 limits the transplanted skin to human skin. Claim 13 of ‘198 recites “The method of claim 12, wherein the transplanted skin has been transplanted onto a human host.” Claim 15 of ‘198 recites “The method of claim 1, wherein the composition further comprises a physiologically compatible carrier” and claim 16 of ‘198 limits the carrier to Vaselinum cholesterinatum. Claim 18 of ‘198 limits the alkaline phosphatase to placental alkaline phosphatase.
Claims 1, 11-13, 15, and 18 of ‘198 do not recite administering human placental alkaline phosphatase to an area of acne vulgaris infected by Propionibacterium acnes bacteria. Claims 1, 11-13, 15, and 18 of ‘198 does not teach that human placental alkaline phosphatase combines with extracellular ATP derived from damaged cells or from Propionibacterium acnes.
Kiss teaches a method for stimulating proliferation and inhibiting the death of skin cells in wounded skin (Abstract). The method includes a step of topically administering to an area of host skin a composition comprising alkaline phosphatase such as placental alkaline phosphatase (Abstract). Kiss teaches that the composition when administered reduces inflammation and microbial infection in the skin (Abstract). Kiss teaches that the administration of placental alkaline phosphatase promotes wound healing and controls inflammation and skin infection ([0002] and [0078]). Kiss teaches administering a therapeutically effective amount of placental alkaline phosphatase in a physiologically compatible carrier ([0076]). Kiss teaches that the placental alkaline phosphatase is human (see [0038]).
Kiss’s composition comprises anti-acne agents ([0096]).
Kiss teaches that inflammation is associated with scarring during healing ([0006]). Kiss teaches that a recent trend among dermatologists it to attempt to reduce the inflammation phase to avoid excessive scarring during healing ([0006]).
Dreno teaches that the pathogenesis of acne (synonym for acne vulgaris, as evidenced by Cleveland Clinic, last line on