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 OFFICE ACTION
This Office Action is in response to the papers filed on 25 November 2025.
PRIORTY
The Applicant claims priority to Provisional Applications 62/697376 (filed on 7/12/2018) and 62/733046 (filed on 9/18/2018). The Provisional Applications do not provide support for the SRC and GPA assays and all of the molecular mass ranges recited in claim 1. The Provisional Applications do not provide support for a depth of 1/8 inch to 2 inches at about a 30 degree angle. Foreign Priority document PCTIB2019000767, filed on 11 July 2019, provides support for a change in score from baseline to Day 71 of about -0.1 to about -2.0 ([section 19 of 000264]). The foreign priority document provides support for the injection angle recited in claim 1. The foreign priority document does not provide support for a depth of 1/8 inch to 2 inches at about a 30 degree angle. The Non-Provisional Application filed on 01/12/2021 provides support for this limitation in Table 15.
CLAIMS UNDER EXAMINATION
Claims 1-3, 5-8 and 11-12 are pending and have been examined on their merits.
MAINTAINED REJECTIONS
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-3, 5-8 and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Hart et al. (previously cited; Method of Treating Or Reducing EFP. US20140335072 2014) in view of PR Newswire (previously cited; Endo Announces Positive Data from Phase 2b Study of Collagenase Clostridium Histolyticum (CCH) in Patients with Cellulite 17 November 2016), Sivagnanam et al. (previously cited; Mesotherapy-The French Connection. J Pharmacol Pharmacother. 2010 Jan-Jun;1(1):4–8) and Mesotherapy Worldwide (Injection Techniques. 2006) as evidenced by Sabatino et al. (previously cited; Compositions and methods for treating collagen-mediated diseases. Patent 7811560).
Hart teaches a method of treating or reducing Edematous fibrosclerotic panniculopathy (EFP) comprising administering injections of collagenase to an area affected by EFP (Abstract). EFP is commonly referred to as cellulite ([0002]). One or more low dose injections of collagenase are effective to reduce or treat EFP ([0005]). Therefore the art teaches administering a therapeutically effective amount of collagenase to treat cellulite. Hart discloses a collagenase comprising a combination of collagenases AUX I and AUX II derived from fermentation by Clostridium histolyticum, and discloses the collagenase has a purity of at least 95% determined by HPLC ([0024]). Therefore Hart meets the limitations of the characteristic vii of claim 1. In Table 3, Hart identifies the administered composition as “CCH”. The following is noted from the Instant Specification ([0104]):
“CCH” as used herein means the AUX-I (Seq. ID No. 5 (FIG. 2)) and AUX-II (Seq. No. ID 6 (FIG. 3)) mixture of collagenases in an approximate 1:1 ratio obtained by the fermentation of Clostridium histolyticum (also known as Hathewaya histolytica). CCH is available commercially as a lyophilized powder under the trademark XIAFLEX®, which comprises the AUX-I and AUX-II mixture with particular excipients, although CCH may be used with other suitable excipients.
The composition taught by Hart comprises AUX-I and AUX-II. As evidenced by the Instant Specification at [0203] Aux-I and AUX-II have characteristics i, ii, iv and v of claim 1. Therefore the composition taught by Hart would possess these characteristics.
Hart does not disclose the presence of lostripain, gelatinase or leupeptin. Therefore Hart meets the limitations of the characteristic xi of claim 1.
Hart discloses the contents of “US Patent 7811560 are expressly incorporated herein by reference herein” ([0024]). Examiner notes this patent is Sabatino et al.
Regarding the bodily incorporation of US Patent 7811560 (Sabatino et al):
Sabatino teaches a drug consisting of collagenase I and collagenase II having the sequence of Clostridium histolyticum collagenase I and collagenase II, respectively, having a mass ratio of about 1 to 1 with a purity of greater than at least 95% by area (Abstract; see column 81, lines 45-49). The art teaches purity is determined by RP-HPLC (reverse phase high performance liquid chromatography (See Table A at Column 19). This meets the limitations of characteristic vii of instant claim 1. The composition comprises less than 1 cfu/ml bioburden and less than or equal to 1% by area of clostripain and gelatinase (see same section). This meets the limitations of characteristics xi and xii of instant claim 1. The composition comprises 13,000-23,000 fSRC units/mg AUX I collagenase (see same section). This reads on characteristic viii of instant claim 1. The composition comprises 230000-430000 fGPA units/mg AUX II collagenase (same cited section). This reads on characteristic ix of instant claim 1.
Therefore the composition taught by Hart possesses the characteristics disclosed in the Sabatino reference.
Hart teaches women (humans) are treated ([0045]). Hart treats the thigh ([0047]). Hart analyzes cellulite using an EFP (cellulite) severity scale (CSS). The CSS is a photonumeric scale that looks at five key morphologic features of EFP: (A) number of depressions, (B) depth of depressions, (C) morphological appearance of skin surface, (D) laxity, flaccidity or sagging of skin, and (E) the classification scale originally described by Nürnberger and Müller ([0020]). Hart teaches the extent of collagen lysis is proportional to the dose volume injected ([0040]).
Hart uses a syringe with a needle to administer a dose of Collagenase Clostridium Histolyticum ([0059]). At each of the 10 sites, study drug will be injected perpendicular to the subject's skin to a depth of ¼ inch (~ 7mm) ([0059]). “Perpendicular” is interpreted to be a 90° angle to a surface.
Hart treats cellulite in the thigh of a human. Hart injections a therapeutically effective amount of a collagenase with the claimed characteristics. Hart analyzes cellulite using a EFP (cellulite) severity scale (i.e. CSS). Hart analyzes dimple depth. Hart teaches injection perpendicular to the subject's skin to a depth of ¼ inch (between a depth of 1/8 inch to 2 inches).
The deficiencies of Hart are: The art does not teach the claimed change in Hexsel Depression Depth Score. The art does not teach injection at the angle recited in claim 1.
Endo (PR Newswire) teaches a method of using clostridium histolyticum (CCH) for the treatment of cellulite (page 1, first paragraph). The art teaches CCH is known in its currently approved indications in the U.S. as XIAFLEX (same cited section). As evidenced by the Instant Specification, the composition taught by Auxilium (Xiaflex) comprises AUX-I and AUX-II ([0104]). As evidenced by the Instant Specification at [0203]) Aux-I and AUX-II have characteristics i, ii, iv and v of claim 1. Therefore the composition taught by Auxilium would possess these characteristics
Endo teaches the following (see last paragraph of page 3 bridging first paragraph of page 4):
The Phase 2b trial enrolled 375 women with moderate or severe cellulite aged 18 years or older in the United States. Each subject received up to three treatment sessions of CCH (0.84 mg / session) or placebo with each treatment session occurring approximately 21 days apart. Twelve injections were administered into cellulite dimples during each session across an entire treatment quadrant – left or right buttock or left or right posteriolateral thigh. At both the outset and conclusion of the study period (28 days after the last treatment), cellulite severity was assessed by each patient and clinician using two photonumeric cellulite severity scales developed by Endo and third-party experts. The scales – the Photonumeric Cellulite Severity Scale (PCSS) – are 5-point scales ranging from 0 (no cellulite) to 4 (severe cellulite) that measure improvement in the appearance of cellulite.
The endpoint of the study is Day 71 (see page 4, second paragraph). Improvement is assessed using changes in the Hexsel cellulite severity scale (same cited section).
Therefore Endo teaches treating cellulite in the buttock or thigh by injection. The art teaches performing an assessment at Day 71. Improvement is analyzed using the Hexsel cellulite severity scale.
Endo teaches a highly significant proportion of CCH subjects were reported as "Improved" or "Very Improved" or "Very Much Improved" in global appearance of their cellulite area (see page 5, bullet point 4).
Sivagnanam et al. teach “mesotherapy” describes a method of drug delivery (page 4, left column, second paragraph). Sivagnanam teaches nappage is a commonly used mesotherapy technique that delivers superficial injections (2 mm deep) injections with a needle covering a large area given at a 45° angle (hence about 30°; see page 6, right column “Nappage” section).
Sivagnanam also teaches the following:
Mesotherapy involves the use of multiple intradermal or subcutaneous injections of a mixture of compounds in minute doses, by means of very fine needles, directly over/near the affected sites. Mesotherapy can be used to remove cellulite in thighs (page 5, right column, third and fourth paragraph). Collagenase is found to be very effective in the elimination of unwanted fat deposits and skin rejuvenation (same cited section). Collagenase disintegrates the bands of fibrous tissue formed between fat lobules in cellulite (see page 4, left column, first two lines).
Mesotherapy Worldwide teaches the mesotherapy technique used for injection varies according to depth (first paragraph). Nappage is the most commonly used technique. Nappage is a superficial intradermal technique which consists of performing a series of injections while maintaining a regular and constant pressure on the plunger. The needle is inserted at an angle of 30°C to 60°C and to a depth of between 2mm and 4mm (see second paragraph of section titled “Nappage”). The product/medication is deposited on the surface of the epidermis and is left in contact with the epidermis to assist in penetration (same cited section).
It would have been obvious to use the Hexsel CSS to analyze dimple depth. One would have been motivated to do so since Hart uses a CSS to analyze dimple depth and Endo uses the Hexsel CSS to analyze changes in cellulite dimples. One would perform analysis at day 71 since Endo teaches doing so for CSS analysis following collagenase treatment. One would have had a reasonable expectation of success since Endo teaches Hexsel CSS can be used to analyze a thigh treated with collagenase at day 71.
It would have been obvious to combine the teachings of the prior art by inserting the syringe at about a 30°angle. Hart teaches a method of treating thigh cellulite by injecting collagenase and Sivagnanam treats cellulite using nappage injections at a 45° angle (about 30 °C). One would optimize the degree of injection because Mesotherapy Worldwide teaches the nappage technique can be performed by inserting the needle at an angle of 30°C to 60°C (about 30 °C) at a depth between 2-4 mm. Mesotherapy Worldwide teaches the injection depth deposits medication on the surface of the epidermis to assist with penetration. The skilled artisan would treat without fully moving the needle from the skin to ensure the entire therapeutic dose is administered to the surface of the epidermis. One would have had a reasonable expectation of success since Sivagnam teaches cellulite can be treated with collagenase using mesotherapy. One would have expected similar results since the references are directed to epidermal injection techniques.
It would have been obvious to optimize the number of aliquots administered. One would do so to delivered the desired amount of therapeutic to the treatment site. One would have had a reasonable since Hart teaches the extent of collagen lysis is proportional to the dose volume injected. One would administer additional volumes (hence, aliquots) of the therapeutic to achieve the desired amount of collagen lysis. One would have had a reasonable expectation of success since both Hart and Endo teach multiple doses (aliquots) can be administered. Because the claimed method is rendered obvious, it would be expected to result in the claimed changed in Hexsel Depression Depth Score at Day 71. Therefore claim 1 is rendered obvious.
Injecting 5 aliquots is rendered obvious on the grounds set forth in the rejection of claim 1 above. Therefore claim 2 is included in this rejection.
Because the composition taught by Hart comprises AUX-I and AUX-II, it would be expected to have the characteristics recited in claim 3. Therefore claim 3 is rejected.
As set forth above, the composition taught by Hart meets the limitations of characteristics i, vii, xi and xii. As evidenced by the Instant Specification at [0203]) Aux-I and AUX-II have characteristics i, ii, iv and v of claim 1. Therefore the composition taught by Hart has at least 5 of the characteristics recited in claim 1. Therefore claims 5-7 are rejected.
Sabatino, which is incorporated by Hart, identifies cellulite as a collagen mediated-disease that may be treated by the disclosed composition (column 21, line 7). The art disclose an exemplary formulation comprising a 0.9 mg drug substance dose (column 24, line 13). 0.9 mg of collagenase is interpreted to be about 1 mg. Therefore claim 8 is included in this rejection.
Hart teaches a collagenase composition for treating cellulite. As set forth above, Hart teaches a collagenase comprising collagenase I and II from Clostridium in a 1:1 ratio with a purity of at least 95%. Examiner notes the Instant Specification discloses a collagenase composition from Clostridium hystoliticum comprising collagenase I and II with the same purity ([00457]). The potency is between 5,000 to about 25,000 ABC units ([0471]). Absent evidence to the contrary, the collagenase taught by Hart is expected to have the potency recited in claim 11. Hart does not explicitly teach administering a dose of about 1 mg as recited in claims 11-12.
Endo teaches subjected receive up to three treatment sessions of CCH at 0.84 g/session (see page 3, last paragraph). While the specification defines the term “about” (supra), it does not disclose the values encompassed by the term “about”. Therefore 0.84 mg is broadly interpreted to read on about 1 mg. It would have been obvious to administer about 1 mg of the claimed collagenase to treat cellulite. One would have been motivated to do so since Hart administers collagenase to treat cellulite and Endo teaches about 1 mg collagenase can be administered to treat cellulite. One would have had a reasonable expectation of success since Endo teaches this amount can be administered to treat cellulite. One would have expected similar results since both references are directed to a method of treating cellulite in a thigh using collagenase. Therefore claim 11 is rendered obvious.
The Hart reference incorporates the contents of the Sabatino Patent. The Sabatino Patent teaches a collagenase composition comprising 0.9 mg collagenase. This is interpreted to be about 1 mg. Sabatino teaches the composition comprises 13,000-23,000 fSRC units/mg AUX I collagenase (see same section). Because neither the instant claims nor specification disclose the values encompassed by the term “about”, Sabatino is broadly interpreted to read on about 20,000 to about 30,000 fSRC units/mg.
Sabatino teaches the composition comprises 230000-430000 fGPA units/mg AUX II collagenase. Because neither the instant claims nor specification disclose the values encompassed by the term “about”, Sabatino is broadly interpreted to read on about 175,000 to about 300,000 f-GPA units/mg. It would have been obvious to administer about 1 mg collagenase to treat cellulite for the reasons set forth in the rejection of claim 11. Therefore claim 12 is rendered obvious.
Therefore Applicant’s Invention is rendered obvious as claimed.
RESPONSE TO APPLICANT’S ARGUMENTS
The arguments made in the response filed on 12 March 2026 are acknowledged.
Argument 1: The Applicant argues Mesotherapy Worldwide teaches a "Point by Point" injection technique is "for the treatment of cellulite”, and uses a perpendicular injection angle. The Applicant argues the Examiner used improper hindsight reasoning.
Response to Argument 1: Claim 1 recites an angle of “about 30°”. While the Applicant argues the prior art does not teach the claimed angle of injection, “about 30°” is not limited to 30°. The term “about” is not defined in the specification. Therefore injection angles above and below 30° read on the claim. Therefore a perpendicular injection angle would read on the claim.
Sivagnanam et al. is relied upon because it teaches mesotherapy/nappage can be used to treat cellulite. Sivagnanam teaches nappage is a commonly used mesotherapy technique that delivers superficial injections (2 mm deep) injections with a needle covering a large area given at a 45° angle (hence about 30°).
Mesotherapy Worldwide teaches the needle is inserted at an angle of 30°C to 60°C and to a depth of between 2mm and 4mm for nappage. Mesotherapy Worldwide teaches the injection depth deposits medication on the surface of the epidermis to assist with penetration.
It would have been obvious to combine the teachings of the prior art by inserting the syringe at about a 30°angle. Hart teaches a method of treating thigh cellulite by injecting collagenase and Sivagnanam treats cellulite using nappage injections at a 45° angle (about 30 °C). One would optimize the degree of injection because Mesotherapy Worldwide teaches the nappage technique can be performed by inserting the needle at an angle of 30°C to 60°C (about 30 °C) at a depth between 2-4 mm. Mesotherapy Worldwide teaches the injection depth deposits medication on the surface of the epidermis to assist with penetration. The skilled artisan would treat without fully moving the needle from the skin to ensure the entire therapeutic dose is administered to the surface of the epidermis. One would have had a reasonable expectation of success since Sivagnam teaches cellulite can be treated with collagenase using mesotherapy. One would have expected similar results since the references are directed to epidermal injection techniques.
Regarding the use of impermissible hindsight reasoning and number of references relied upon:
Treatment cellulite in a human thigh by administering collagenase is taught by the prior art. As set forth above, the prior art teaches mesotherapy/nappage is well known technique used to treat cellulite. An injection angle of about 30 degrees is known. Therefore the condition and method of administration are disclosed in the prior art. The rejections rely upon the composition and method of administration taught in the prior art. Reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention Therefore the argument is not persuasive. See MPEP 2145 X. A. and V.
Argument 2: The Applicant argues Examiner changes the rationale for rejecting the claims in the Non-Final Office Action.
Response to Argument 2: Examiner made new grounds of rejection in the last Non-Final Office Action to address the new limitation recited in the amended claims. Therefore the argument is not persuasive.
Argument 3: The Applicant argues the rejection disregards Sivagnanam's repeated negative statements regarding the use of mesotherapy
Response to Argument 4: Sivagnanam teaches nappage “is a commonly used mesotherapy technique”. The art teaches mesotherapy can be used to remove cellulite in thighs (page 5, right column, third and fourth paragraph). Collagenase is found to be very effective in the elimination of unwanted fat deposits and skin rejuvenation (same cited section). Collagenase disintegrates the bands of fibrous tissue formed between fat lobules in cellulite (see page 4, left column, first two lines). Therefore the art teaches nappage is a technique that can be used to treat cellulite. While the art teaches injections are given at a 45° angle, this angle reads on the claim limitation.
The Applicant argues Sivagnanam teaches away from mesotherapy. This argument is not persuasive for the same reasons state in the last Office Action: Sivagnanam teaches “About 16,000 US physicians use mesotherapy in their daily medical practice, the growth of number of mesotherapy-trained physicians by 300 per month” (see page 7, right column, third paragraph). While Sivagnanam teaches there are a “dearth of rigorous scientific studies”, the reference concludes by stating “lack of scientific validation is not proof that it does not work” (see last paragraph of page 7).
Sivagnanam teaches “Mesotherapy is the buzz word in the cosmetic world of “melting fat” for weight loss and cellulite treatment. It is also a form of “injection lipolysis”. Presently, mesotherapy is gaining lure mainly for non-surgical cosmetic applications, like removal of disfiguring fat (cellulite) in thighs, buttocks, hips, legs, arms, and facial areas”. Therefore the art does not teach away from the nappage technique recited in the rejection. The arguments are not persuasive.
CONCLUSION
No Claims Are Allowed
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653