DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims status
Amendments filed 08/27/2024 are entered. Claims 16-35 are pending and under examination.
Priority
This application is a 371 application, filed 08/27/2024, of PCT application PCT/EP2023/054925, filed 02/28/2023, which claims priority benefits from Foreign Application No. EP22159241.3, filed 02/28/2022. The effective filing date of this application is 02/28/2022, the filing date of EP22159241.3.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 11/13/2024 and 08/27/2024 are being considered by the examiner.
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.
Claims 24, 27-35 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.
Claims 24, 27-35 recite “across” the forehead and/or both cheeks but it is unclear the boundaries of what “across” means. The specification provides some examples of injection sites or injection site patterns in the forehead region and how they can be distributed (e.g. instant Figure 1), but there is no limiting definition in the disclosure or commonly understood definition of what constitutes “across” the forehead or cheek, and what does not. Must the injection sites span a specific area or distance of the forehead or cheek? Must the injection site cover the forehead or cheek in both the vertical and horizontal direction. Is one injection sufficient to constitute “across” or does not it necessitate multiple? Does “across” include injections that span only a small area on the forehead?
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claims 16-24 are rejected under 35 U.S.C. 103 as being unpatentable over Li (Li et al, Regulation of lipid production by acetylcholine signalling in human sebaceous glands; published 2013) in view of Wu (Wu et al, US 20200108129 A1; published 04/09/2020).
The scope of claim 16 encompasses injections of all combinations of botulinum concentrations of 11 U/ml to 19 U/ml and all injection volumes of 0.07 ml to 0.12 ml. These combinations amount to 0.77 U to 2.28 U per injection.
Regarding claim 16, Li teaches method for reduction of skin pore size and/or sebum production, the method comprising administering botulinum toxin by intradermal injection into skin of a subject (Abstract and p. 118, col. 1). Li further teaches 0.1 ml per injection point. Li et al teaches an injection concentration of 2 U/0.1 ml, which equals 20 U/ml, which is 2 U per injection site.
Li further teaches that botulinum toxin A is a neurotoxin that blocks the release of acetylcholine, and is used in several treatments and motivating off-label cosmetic applications (p. 121, col. 2, para. 2). Li teaches that botulinum effectively reduced sebum production and pore size, which supports that sebum production is influenced by cholinergic (i.e. acts upon neurotransmitter acetylcholine) signaling and that botulinum decreases sebum production by interfering with cholinergic transmission to sebaceous glands (p. 122, col. 1, para. 1).
Li does not explicitly teach an injection concentration of 11 U/ml to 19 U/ml.
However, Wu teaches a composition called “2.96 U/kg control” which has a botulinum concentration of 17.9 U/ml and contains other pharmaceutical excipients (p. 11, Table 2). Wu further teaches a composition called “2.84 U/kg BONT/A in Saline” which is the botulinum in saline only (Figure 3 and p. 12, para. 0150-0151), tested in Example 3 in the same manner as “2.96 U/kg control”, with the results shown in Figure 3. From this information, the mass of the rat subject is around 0.3 kg and the concentration of the “2.84 U/kg BONT/A in Saline” is about 17.2 U/ml.
Wu teaches these compositions comprising of botulinum toxin are useful in methods for treating various diseases, disorders, and conditions, including skin conditions, which include excess sebum production (p. 6-7, para. 0093); and neuromuscular diseases (p. 24, para. 0230). Based on the efficacy of their botulinum compositions, Wu further envisions a method for treating a skin disorder comprising local administration of the botulinum neurotoxin composition to a location of a skin disorder, such as to the face; wherein the neurotoxin can be administered at multiple sites (p. 28, para. 0259), where the sites are separated by certain distances (p. 28, para. 0259-0260). Wu et al teaches the botulinum can be administered at specific doses (p. 28, para. 0259-0260), and can be administered according to the weight of the patient (p. 28, para. 0258), manufactures’ specifications, the class of the toxins, the mode of administration, and the frequency of re-administration (p. 28, para. 0259).
Regarding the “2.96 U/kg control” and “2.84 U/kg BONT/A in Saline” compositions (botulinum concentrations of 17-18 U/ml), Wu compares their DAS to other compositions, such as those with higher botulinum concentrations, e.g. 28.2 U/ml, called “4.70 U/kg control” (p. 11, Table 2 and Figures 1A-1B) and “5.06 U/kg BONT/A in Saline” (Figure 3). Wu teaches through these figures that botulinum exhibits potency at both concentrations, with a mean DAS of at least around 2 out of 4 (max potency) at its peak, and the higher concentration botulinum injection has a higher potency than the lower concentration botulinum injection.
Wu et al does not explicitly teach the results of their composition in reducing skin pore size and/or sebum production. However, they teach the compositions in Example 2-3 tests, which comprises of intramuscular injections into the tibialis anterior of a rat (p. 11, para. 0146 and Example 2 on p. 30), the Digital Abduction Score (DAS), which measures the local muscle weakening efficacy of botulinum toxin, derived from these tests are a measure of the botulinum toxin’s physiological potency (p. 1, para. 0008). This DAS score is generalizable for the physiological potency of botulinum and an indicator for its ability to block acetylcholine release, which is the mechanism of action underlying both its ability to weaken muscle and reduce sebum production.
Wu does not explicitly teach a volume of 0.07 ml to 0.012 ml per injection but teaches a 50 ul (0.05 ml) injection volume in their Example 2-3 tests for rat models (p. 30, para. 0277-278).
In summary, both Li and Wu teach a total injected botulinum, by units (U), that falls within the scope of the claim (0.77 U to 2.28 U per injection) but by different concentration or volume. Li differs from the instant application by the injection concentration, teaching 20 U/ml. Wu differs from the instant application by the injection volume, teaching 0.05 ml. Wu teaches that nonlimiting administration parameters and that one skilled in the art would know when alternative embodiments are applicable.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, in light of the teachings of Li regarding the efficacy of about 20 U/ml botulinum in a 0.1 ml dose in reducing sebum production and pore size and the teachings of Wu regarding the potency of about 17-18 U/ml botulinum in a 0.05 ml dose, to try the claimed lower concentrations taught by Wu in the base method taught by Li. Li teaches the potency of botulinum at about 28 U/ml and 17-18 U/ml in a 0.05 ml injection volume and shows that although botulinum would be expected be less potent at the lower concentration and dose volume, it would still have measurable potency (by DAS) at 17-18 U/ml; that is, these concentrations are not too low to exhibit measurable potency. Since sebum production reduction is linked to acetylcholine blockage, it is expected that the teachings of Wu regarding the DAS score of different botulinum concentrations, as an indicator of acetylcholine blockage, is also an indicator of the expected effect size of reducing skin pore size and/or sebum production by botulinum. In other words, botulinum is expected to have potency across, at least, a range of concentrations and dosages. If botulinum has potency at 17-18 U/ml in a 0.05 ml dose, it likely will also have potency at 17-18 U/ml in the 0.1 ml dose taught by Li. If botulinum reduced sebum production at 20 U/ml in a 0.1 ml dose, it is likely it will also reduce sebum production at a 17-18 U/ml dose, based on its exhibited potency. As the claims do not claim any specific degree of reduction or other metric, this expected effect by the 17-18 U/ml dose, even if it is less than the effect of the 20 U/ml dose, falls within the scope of the claims, and is furthermore, expected.
One skilled in the art, before the effective filing date of the instant application, would be motivated to try a lower concentration of botulinum that is still effective in reducing skin pore size and/or sebum production, depending on the severity of the initial skin problem and the desired degree of effect. One would be motivated to use this concentration in reducing sebum production, in light of the direct teachings by Wu and the teachings by Li that their botulinum composition could also be used for this purpose.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success because of the characterized potency of botulinum, indicating its effectiveness in blocking acetylcholine at the instantly claimed concentration, as taught by Wu, and the teachings by Li that botulinum, by way of its acetylcholine blockade, can reduce sebum production and pore size at a similar condition (intradermal injection of 0.1 ml of 20 U/ml) as the instantly claimed method.
Claims 17-24 depend on claim 16. The teachings of the references regarding the parent claims are incorporated in their entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claims 17-18, the concentration taught by Wu, at about 17-18 U/ml, used to modify the method taught by Li (20 U/ml, 0.1 ml injection) still falls within the claimed range.
Regarding claims 19-20, the volume per injection point taught by Li, 0.1 ml, still falls within the claimed range.
Regarding claims 21-23, as previously presented, the combination of Li in view of Wu teaches administrating 17-18 U/ml in a 0.1 ml injection, meeting the limitations of claim 23, and which amounts to 1.7-1.8 U per injection point, meeting the limitations of claims 21-22.
Regarding claim 24, Li teaches injection of botulinum into one cheek and saline, as a control, into the other cheek of a subject to compare the difference.
Wu also teaches that in treating skin conditions, the botulinum is administered to the location of the skin disorder.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that the botulinum treatment could be administered to both cheeks that need sebum reduction, and that one cheek was used as a control just to show a difference between the botulinum and the saline in the same subject. One skilled in the art, before the effective filing date of the instant application, would be motivated to treat both cheeks, and would have reasonable expectation of success that the effects seen on one cheek is the same for the other cheek and a subject can be treated on both cheeks at the same time. Li in view of Wu reads on the limitations of claim 24 since the injection into the forehead is an alternative limitation.
Claims 25-35 are rejected under 35 U.S.C. 103 as being unpatentable over Li in view of Wu, as applied to claim 16 above, and further in view of Park (Park et al, Intradermal Microdroplet injection of diluted Incobotulinumtoxin-A for Sebum Control, Face Lifting, and Pore Size Improvement, published 01/2021), Min (Min et al, Sebum Production Alteration after Botulinum Toxin Type A Injections for the Treatment of Forehead Rhytides: A Prospective Randomized Double-Blind Dose-Comparative Clinical Investigation, published 03/30/2015), and Kesty (Kesty et al, A Randomized, Double-Blinded Study Evaluating the Safety and Efficacy of AbobotulinumtoxinA Injections for Oily Skin of the Forehead: A Dose–Response Analysis, published 01/2021).
Claims 25-35 depend on claim 16. The teachings of the references regarding the parent claim and claim 24, which is relevant to the below claims, are incorporated in their entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claims 25-35, Li in view of Wu teaches injection into both cheek, as discussed for claim 24. Li teaches administering 0.1 ml of 2U/0.1 ml injections at 4 injection points 1 cm apart on the cheek, which amounts to 2U x 4 injections x 2 cheeks = 16 U total dose.
Regarding claims 25-35, Li in view of Wu do not explicitly teach injection into or across the forehead although Wu teaches injection into the site of affliction.
However, Park teaches the forehead is also a site of sebum production, and botulinum intradermal injection into the forehead, particularly the mid-glabella area, and into both cheeks to reduce sebum production and facial pore size (Abstract and Figure 1).
Park teaches 10 injections on each cheek (Figure 1).
Park teaches administering 0.5 U injections at 10 injection points per cheek, distributed across the cheek, and one 5 U injection on the mid-glabella area of the forehead, which amounts to (0.5 U x 10 injections x 2 cheeks) + (5 U x 1 injection x 1 forehead) = 10 U for cheeks + 5 U for forehead = 15 U total dose by 11 total injections.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that since the forehead is also a site of sebum production and that botulinum injection into the mid-glabella of the forehead also reduces sebum production and pore size in this area, the botulinum injection could also be given to the forehead, in addition to the cheek.
One skilled in the art, before the effective filing date of the instant application, would be motivated to reduce sebum production and pore size in skin areas that are afflicted, especially one as visible as the forehead and cheeks, as taught by the combination of prior art references.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success due to botulinum shown to already work as described when injected into the cheek and the forehead. Even though the doses in Park may be slightly different from those taught by Li in view of Wu, Park is used to teach the affected regions, as Li in view of Wu already shows success in the cheek, which gives likelihood of success in foreheads.
Further regarding claims 25-26, Li in view of Wu and Park do not explicitly teach the claimed total dose administered to the forehead and both cheeks.
Further regarding claims 27-35, Li in view of Wu and Park, teaching the method comprising of one injection site in the forehead in the mid-glabella area, does not explicitly teach injection across the forehead, interpreted to signify multiple injections spread across the forehead.
Further regarding claims 27-28, Li in view of Wu and Park, do not explicitly teach the total number of injection points distributed across the forehead and both cheeks. Park teaches a total of 11 injection points across the forehead and cheek.
Further regarding claims 29-31, Li in view of Wu and Park do not explicitly teach the number of injection points across the forehead and number of injection points per cheek (29-31)
Further regarding claims 31-33, Li in view of Wu and Park do not explicitly teach the orientation of the injection points on the cheek and forehead
Further regarding claims 34, Li in view of Wu and Park do not explicitly teach the distance between the injection points on the cheek and forehead.
However, regarding claims 25-35, Min teaches 5 botulinum injection across the forehead leading to reduced sebum production (Abstract and Figure 1).
Min differs from the instant application by teaching intramuscular injections into the forehead instead of the instantly claimed intradermal injection.
However, this is because they wanted to see if an intramuscular botulinum injection method used to treat forehead rhytides (i.e. wrinkles) also has the added benefit of reducing sebum production (Abstract), but provides motivation for an intradermal injection. First, Min teaches that the sebaceous follicle, responsible for sebum production, is located intradermally (p. 606, col. 2, para. 1). Min further notes that other studies in the art using intradermal injection to treat sebum production has a higher efficacy than their study using intramuscular injections, likely due to the intramuscular botulinum having to diffuse from the muscle layer into the dermal layer, leading to a diluted effect in the dermal layer (p. 608, col. 1, para. 1 – col. 2, para. 1).
However, also regarding claims 25-35, Kesty teaches 12 botulinum injections intradermally across the forehead (Figure 1 and p. 57, section: Materials and Methods, para. 1) to treat oil skin and reduce pore size by reducing sebum production (Abstract and p. 56 , col. 1, para. 2 to col. 2, para. 2).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that between the intradermal injections to reduce sebum production in the forehead and cheek taught by the other prior art references and the intramuscular injection taught by Min that also works, but to a lesser degree, the intradermal injection is likely the better choice to reduce sebum production, especially also in light of the teachings by Kesty.
One skilled in the art, before the effective filing date of the instant application, would be motivated to choose intradermal injection to deliver the botulinum directly to the sebaceous follicle in the intradermal layer for the advantage of utilizing the full potency of botulinum at the afflicted site.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success with choosing intradermal injection due to the superiority of the intradermal route for sebum production reduction when compared to intramuscular injections, as taught by Min and Kesty.
Further regarding claims 25-35, Park further teaches administration into parts of the face where sebum and pore size reduction is desired, including the forehead and cheek, amounting to a total dose administered to the face of 92 U by 64 injections (Figure 1), indicating that these number of injections and dosage to the face is still tolerable.
Min further motivates botulinum injection into the forehead to reduce sebum production by teaching forehead region normally has higher sebum production than other regions of the face because of higher density of sebaceous follicles (p. 601, col. 1, para. 2).
Min teaches 5 injections across the forehead at 2 U or 4 U per injection point, totaling 10 U or 20 U, both doses having similar efficacy (Abstract, Table 1, and Figure 1). However, Min also teaches that the area of effect only covers a circular area with a radius of about 1.5 cm around the injection point, not covering the entire forehead.
Kesky teaches 12 injections across the forehead (Figure 1) totaling 30 U or 45 U to be efficacious in reducing sebum/oiliness (Abstract) with more perceived effect with increased dose (p. 59, col.2, para. 2).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to further the method of injecting botulinum in both cheeks and into one location in the forehead, taught by Li in view of Wu and Park, by injecting in multiple locations across the forehead, as taught by Min and Kesky, and inject additional locations across the forehead, as taught by Kesky, in light of Min teaching the effect waned with distance from the injection point so that the 5 injections in the middle of the forehead was insufficient to treat the entirety of the forehead.
One skilled in the art, before the effective filing date of the instant application, would be motivated to treat the entirety of the forehead by injecting at more sites spanning the afflicted area instead of just the middle of the forehead.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success due to the teachings of Kesky et al and the high dose tolerance in the face taught by Park.
For similar reasons, one skilled in the art would also be motivated to choose multiple injections covering the cheek area, choosing the 10 injection pattern taught by Park over the 4 injection site taught by Li.
Therefore, with the previously presented teachings to combine injections into the forehead and into both cheeks, such as from Park:
(10 injections/cheek x 2 cheeks x 0.5U/injection = 10 U total into cheeks by 20 injections) + 1 injection/glabellar region x 5 U/injection = 5 U total into glabellar by 1 injection, the total dose to the forehead and both cheeks based on the combination of references would be
10 U (20 cheek injections, Park) + (5 U (1 glabellar injection, Park) + 40 U (12 forehead injections, Kesky)) = 55 U with 33 injections distributed across the forehead (13 forehead injections) and both cheeks (10 injections per cheek), wherein the forehead comprises the glabellar area.
This injection pattern meets all the limitations of claims 25-29.
The teachings regarding claims 25-29 are also relevant to claims 30-35 and incorporated for these claims.
Further regarding claims 30-33 and 35, the teachings of Li in view of Wu, Park, Min, and Kesky regarding the claimed number of injection points across the forehead is previously presented. However, Li in view of Wu, Park, Min, and Kesky does not explicitly teach 9 injection points per cheek. However, seeing that Min teaches 4 injection points per cheek and Kesky teaches 10 injection points per cheek wherein 9 are arranged as instantly claimed in claim 31 and the 10th is right below the grid of 9 (Figure 1), the instantly claimed 9 injection point and its claimed arrangement is an obvious variant of Kesky.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that there is likely a range of acceptable number of injections depending on the severity of the sebum production, individual sebaceous gland distribution across the cheek, and that the variability in the art is not due to the unpredictability of the art but due to versatility of botulinum to be customized according to the needs of the patient, which is within the abilities of one skilled in the art. Therefore, it would be obvious to a person skilled in the art to try remove the 10th injection point from Kesky if the patient does not need it.
One skilled in the art, before the effective filing date of the instant application, would be motivated to reduce the number of injections while still providing full coverage of the afflicted region, arriving at the 9 injection points claimed.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success even with 4 injections across a cheek, Li was able to show a marked decrease in sebum production. Therefore, it is obvious for a person skilled in the art to choose between 4-10 injections per cheek as needed, and have reasonable expectation that sebum production will be reduced to varying degrees depending on the dose and severity of the affliction.
Further regarding claims 32-33, Li in view of Wu, Park, Min, and Kesky do not explicitly teach the orientation of the injection points on the forehead.
However, Kesky also teaches 12 forehead injections and differs slightly from the injection pattern of the instant application. Kesky teaches 2 horizontal rows of 6 injections, clearly neglecting the glabellar region and other parts of the forehead T zone, which Min teaches is an area of high sebum production (p. 601, col 1, para 2).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to distribute the forehead injections to cover the T zone, and particularly the glabellar region, especially since Park teaches injection into the glabellar region to reduce sebum production and since Min teaches the importance of distributing the injections because the circle of diffusion may not cover the necessary area. It will be obvious to one skilled in the art to rearrange the 12 forehead injections taught by Kesty et al to better cover the glabellar region, while maintaining about 1.5 cm distance between each of them and avoiding the eye region.
One skilled in the art, before the effective filing date of the instant application, would be motivated to cover not just the forehead covered in Kesty, but also the glabellar region covered in Park, and, in general, cover the T zone area that is most visible at the front of the face, focusing less on the lateral region of the forehead or the temples, which may have less sebum production at baseline.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success that focusing a local treatment of botulinum to the regions of most sebum production, particularly the T zone of the forehead, would yield the most treatment effects to this area.
Regarding claims 34, Li in view of Wu, Park, Min, and Kesky do not explicitly teach the distance between the injection points on the cheek and forehead.
However, although Park does not explicitly teach the intervals of their cheek injection, Li teaches 1 cm intervals between their 4 cheek injections (p. 118, co1. 1, para. 1), meeting the limitation of the claims regarding the cheek injections.
Regarding the interval between the forehead injections, Kesty teaches approximately 1 cm intervals between their 12 forehead injections (p. 57, col. 2, para. 1). Further, Min teaches that the diffusion circle area of 2 U or 4 U botulinum has a radius of 1.5 cm (p. 602, col. 2, para. 3), and the effect of 2 U or 4 U botulinum injections in Area 1 (0.5 cm radius around injection point), Area 2 (1.5 cm radius around injection point), and Area 3 (2.5 cm radius around injection point) (Figure 2), showing the average sebum production reduction is greatest in Area 1, with some ability to at least maintain or minimally reduce sebum in Area 2 for a period of time, whereas there is a compensatory increase in sebum in Area 3 (Figure 8, and p. 608, col. 2, para. 2). The average sebum production change in Area 1 and Area 2 together is still net negative, about (-)10% after about 8 weeks. Again, Min teaches this with intramuscular injections and further notes that other studies in the art using intradermal injection to treat sebum production has a higher efficacy than their study using intramuscular injections, likely due to the intramuscular botulinum having to diffuse from the muscle layer into the dermal layer, leading to a diluted effect in the dermal layer (p. 608, col. 1, para. 1 – col. 2, para. 1). Therefore, it is likely that the effects may be better in Area 2 with intradermal injections.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that an injection point will still have a net negative sebum production in the circular area around it with a 1.5 cm radius and the greatest within a 0.5 cm radius, conferring a distance of at most 3 cm and at least 1 cm between injection points, depending on the severity of the sebum and the botulinum dose. One skilled in the art would be motivated to have some overlap of potency, especially if using a lower dose than 2 U or 4 U per injection site. Therefore, one skilled in the art may be motivated to choose 2 cm as a midpoint between the 1 cm distance, to prevent wasteful administration in overlapping areas of diffusion, and 3 cm, which may leave the boundaries of the diffusion area without sufficient botulinum. One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success within this range of distances due to the diffusion profile and expected effect within the area of diffusions.
Regarding claim 35, Li in view of Wu and Park all teach a 150 kDa botulinum toxin with (Li and Wu) and without (Park) complexing proteins.
For convenience, relevant figures are reproduced or annotated and reproduced below for comparison.
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(Figure 1 of Park et al) (Figure 1 of Min et al)
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(Figure 1 of Kesty et al) (Figure 1 of instant Drawing)
In summary, the broad scope or range of acceptable doses, injection sites arrangement, number of injection sites, and total doses bely the utility and tolerability of botulinum, not the unpredictability of botulinum. The regions to target to reduce sebum production or pore size are known in the art. Acceptable botulinum injection sites are known in the art. Also known in the art are efficacious doses per injection site, the spread distance from the injection point for common doses, and the approximate time the effect lasts. Using this information, it is within the scope of one skilled in the art, to administer the botulinum according to the needs and desires of the patient. A person skilled in the art that desires full coverage of the forehead, would distribute the injections across the forehead so that the radii of effect from all those injection points covers the entire forehead. A person skilled in the art would know what doses to choose to achieve the desired spread area without being wasteful. A person skilled in the art would know what total dose is acceptable. The instant applications claims obvious embodiments of botulinum administration already known in the art. There is no indication that this specific claimed administration has any effects that would be unpredictable to one skilled in the prior art.
Conclusion
No claims are allowed.
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/BONIRATH CHHAY/Examiner, Art Unit 1645
Monday, June 22, 2026
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 June 25, 2026
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