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 .
Claim Rejections - 35 USC § 112
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.
Claims 1, 5-7, 9-17 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the specifically exemplified topical administration of RORCi under the conditions disclosed in the specification, does not reasonably provide enablement for the full scope of the claimed methods involving RORC-product inhibitors, RORγ inhibitors, RORγt inhibitors, inhibitors of both RORγ and RORγt, and combinations thereof for achieving the recited inhibition of keratinocyte-derived malignancy, UV-induced cutaneous carcinogenesis, actinic keratosis, and/or squamous cell carcinoma without undue experimentation. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The Examiner has considered each of the Wands factors as follows.
Breadth of the claims
This factor weighs substantially against enablement.
Claim 1 broadly encompasses repetitive topical administration of “at least one topical inhibitor of an RORC product” in a concentration and for a time sufficient to inhibit RORC-product activity and thereby inhibit development of a keratinocyte-derived malignancy characterized by p53 mutations. Claim 5 similarly encompasses any topical RORC-product inhibitor capable of inhibiting one or more of keratinocyte genotoxicity, epidermal proliferation and dedifferentiation, and mutant-p53 keratinocyte clonal expansion. Claim 6 further encompasses use of the same broad genus to inhibit actinic keratosis and squamous-cell carcinoma.
The claims do not define the RORC-product inhibitors according to a common chemical structure. Rather, operative scope is substantially defined by the biological activity of the compounds. Claim 7 encompasses an RORγ inhibitor, an RORγt inhibitor, or an inhibitor that inhibits both RORγ and RORγt. Claims 9–12 further broaden the practical variables by requiring two or more inhibitors or two or more inhibitor types. Claim 9 encompasses two or more inhibitors that inhibit both RORγ and RORγt; claim 10 encompasses two or more RORγ inhibitors; claim 11 encompasses two or more RORγt inhibitors; and claim 12 encompasses two or more types of RORC inhibitors selected from the recited functional classes.
The specification itself reflects the chemical breadth encompassed by these functional classes. Identified RORC inhibitors include ML209, RORCi, T0901317, digoxin, ursolic acid, SR1001, SR2211, TMP778, VPR-66, GSK805, and GSK2981278, among others. Thus, the claims extend substantially beyond the single inhibitor actually demonstrated to produce the relied-upon carcinogenesis-related effect.
Nature of the invention
This factor weighs against enablement.
The claimed invention involves the biological effect of pharmacologically distinct compounds after topical delivery through the skin for modulation of an immune pathway implicated in a multistep carcinogenic process. Successful practice therefore depends upon several interrelated properties, including receptor potency and selectivity, physicochemical characteristics of the particular compound, cutaneous penetration, local tissue concentration, target engagement, dose, dosing interval, and the resulting biological response.
The specification recognizes the importance of formulation and cutaneous delivery by teaching that the inhibitor may be formulated with a vehicle or carrier that promotes penetration through the stratum corneum into viable epidermal and dermal cells. It identifies solutions, sprays, gels, ointments, creams, lotions, pastes, foams, patches, nanoparticles, and other delivery approaches. These teachings demonstrate that receptor-inhibitory activity alone does not resolve whether a particular compound will be delivered into the relevant skin compartment in an amount sufficient to achieve the claimed effect.
The pertinent art similarly establishes that a topically administered drug must cross the stratum-corneum barrier and that cutaneous delivery is affected by such compound- and formulation-dependent properties as diffusibility, vehicle solubility, partition coefficient, and the vehicle itself.
The invention therefore resides in a pharmacological and biological field in which successful topical receptor inhibition cannot reasonably be treated as a predictable consequence of merely identifying a compound as an RORγ or RORγt inhibitor.
State of the prior art
This factor weighs against enablement of the full scope.
The pre-filing art demonstrates considerable variability among known RORγ/RORγt inhibitors. Skepner et al. reported that previously described small-molecule RORγt inhibitors exhibited variable levels of efficacy in vivo. TMP778 inhibited mouse Th17 differentiation with substantially greater potency than digoxin, and digoxin, SR2211, SR1001, and ursolic acid were reported to have substantially lower potency than TMP778. Several of these compounds are expressly identified in the present specification.
Thus, the state of the art did not establish that compounds falling within the common functional category “RORγt inhibitor” possessed equivalent potency or equivalent biological efficacy. Selection of a member of the claimed functional genus would not, without further testing, establish the dose or topical exposure required to obtain the claimed biological result.
The art concerning GSK2981278 further demonstrates this uncertainty. Smith et al. characterized GSK2981278 as a selective RORγ inhibitor but expressly recognized that in-vitro activity does not necessarily predict behavior in a complex in-vivo system. Topical administration of 1% GSK2981278 in the reported mouse psoriasis model resulted in only a partial reduction in epidermal thickness.
More significantly, before the effective filing date, GSK2981278 had been evaluated clinically at concentrations of 0.03%, 0.1%, 0.8%, and 4%. The GSK study record states that the first clinical study did not show a reduction in psoriatic infiltrate thickness and that it remained uncertain whether the lack of effect resulted from treated surface area, exposure duration, or other treatment conditions.)
This evidence is not relied upon to establish that GSK2981278 cannot practice the claimed invention. Rather, it is relied upon as objective evidence concerning the state and predictability of the pertinent art. It demonstrates that substantial receptor activity and successful preclinical experimentation did not permit the therapeutic effect of a topically administered RORγ inhibitor to be predicted without compound-, formulation-, and regimen-specific experimentation.
The state of the art concerning the claimed AK/SCC endpoint also provides limited predictive guidance. Haque et al. reported that relatively few studies had examined drug disposition in cancerous skin or actinic keratosis. Thus, the prior art would not have supplied a generally accepted relationship permitting a skilled artisan to extrapolate from receptor inhibition or reduction of mutant-keratinocyte clonal area to effective topical treatment or prevention of AK or SCC across the entire claimed inhibitor genus.
Level of ordinary skill in the art
This factor weighs in favor of enablement, but is insufficient to overcome the other factors.
One of ordinary skill would have possessed substantial knowledge in such relevant disciplines as medicinal chemistry, receptor pharmacology, dermatological formulation, cutaneous drug delivery, immunology, and cancer biology, either individually or through a multidisciplinary research team. Conventional methods for measuring receptor inhibition, preparing topical formulations, measuring skin penetration, and evaluating biological responses were known.
However, a high level of skill does not provide the missing predictive relationship between membership in the claimed RORC-inhibitor functional genus and successful topical inhibition of the claimed carcinogenic endpoints. The cited literature demonstrates that skilled investigators actually performed compound-specific potency assays, formulation studies, animal studies, skin-delivery studies, and clinical testing precisely because therapeutic performance could not reliably be inferred from receptor activity alone.
Level of predictability in the art
This factor weighs substantially against enablement.
The evidence establishes that RORγ/RORγt inhibitors vary considerably in potency and in-vivo activity even though they share the recited receptor-inhibitory function. Skepner demonstrates materially different activity among TMP778, digoxin, SR2211, SR1001, and ursolic acid.Smith demonstrates that an inhibitor exhibiting potent in-vitro RORγ activity required separate in-vivo evaluation and produced only partial activity in a topical mouse model. The subsequent clinical experience with GSK2981278 further demonstrates that increasing topical concentrations up to 4% did not predictably yield the expected tissue response.
Topical exposure presents an independent source of unpredictability because compounds having different physicochemical properties may exhibit substantially different skin penetration and local bioavailability.
Accordingly, neither identification of a compound as an RORγ/RORγt inhibitor nor application of a nominal concentration such as 1% provides a predictable basis for determining whether the compound will penetrate the skin, engage the desired target at an effective concentration, and produce inhibition of the recited carcinogenic endpoint.
Amount of direction or guidance provided by the specification
This factor weighs partly in favor of enablement but does not provide sufficient guidance for the full claim scope.
The specification provides substantial general guidance. It identifies exemplary RORC inhibitors and discloses exemplary concentrations from approximately 1 mg/mL to 100 mg/mL or more. It describes repeated administration schedules ranging from multiple daily applications to weekly or monthly administration and expressly discloses once-daily and twice-daily dosing. It also describes numerous topical dosage forms and specifically discloses a 1% formulation.
The specification, however, does not disclose a general structure-activity, physicochemical, pharmacokinetic, or formulation relationship by which one of ordinary skill could determine which otherwise untested RORγ inhibitors, RORγt inhibitors, or dual inhibitors will have the combination of potency, skin penetration, local exposure, and target engagement necessary to produce the claimed result.
The absence of such guidance is more significant for claims 9–12. Although the specification contemplates combinations of inhibitors, it teaches that, when a combination is employed, the concentration may refer either to each inhibitor or to the combined inhibitors and may extend to 100 mg/mL or more “as needed.” The disclosure provides no predictive rule for determining which inhibitors should be combined, their relative concentrations, whether their skin penetration characteristics are compatible, or whether the combination will provide the claimed biological response.
Thus, the disclosure gives the skilled artisan a starting point for experimentation, but does not provide direction commensurate with the functional breadth of the claims.
Existence of working examples
This factor weighs materially against enablement of the full claimed scope.
The specification contains an operative working example involving RORCi, an inhibitor of RORγ and RORγt. RORCi was administered topically once daily for two weeks over a 4-cm² area of UVB-exposed mouse skin in a 1% solution containing 60% ethanol and 40% water. The reported result was approximately a 60% reduction in mutant-keratinocyte levels or clonal area. The specification also describes Figure 3A as showing a decrease in mutant-p53 cells per island after two weeks of RORCi administration.
The working example is credited for what it reasonably demonstrates. The rejection is therefore not predicated merely upon the presence of only one working example. Rather, the concern is the disparity between that example and the scope sought.
There is no working example demonstrating the claimed result with a selective RORγ inhibitor, a selective RORγt inhibitor, another dual inhibitor, any two-inhibitor combination recited by claims 9–12, or an RORC inhibitor in combination with an additional agent as recited by claim 17. More importantly for claim 6, the RORCi experiment measures mutant-keratinocyte clonal expansion. It does not report occurrence, regression, progression, clearance, or prevention of actual actinic keratosis or squamous-cell carcinoma.
Although a specification need not exemplify every species within a genus, MPEP § 2164.02 recognizes that the significance of the number and nature of examples depends upon whether the disclosed examples reasonably correlate with the scope sought. Here, the objective evidence regarding variability among ROR inhibitors, cutaneous penetration, and topical therapeutic performance supplies a technical basis for concluding that the single RORCi example cannot reasonably be extrapolated throughout the full functional genus.
Quantity of experimentation required
This factor weighs substantially against enablement.
To practice presently unexplored portions of claims 1, 5–7, and 9–17, one of ordinary skill would be required to select a candidate RORC inhibitor; determine its potency and relevant isoform activity; identify a vehicle in which the compound can be formulated; determine whether the compound penetrates the stratum corneum and reaches the relevant skin compartment; establish a therapeutically useful local concentration; determine application frequency and duration; and test whether the resulting regimen produces the claimed inhibition of carcinogenesis.
For claims 9–12, additional experimentation would be necessary to identify two or more compounds, determine the concentration of each component, evaluate the effect of combination formulation upon solubility and skin delivery, and determine whether the combination achieves the claimed biological endpoint.
For claim 6, experimentation would further be required to establish that the selected RORC inhibitor and regimen actually inhibit development or progression of actinic keratosis and squamous-cell carcinoma, rather than merely reducing mutant-p53 keratinocyte clonal area in the disclosed mouse model.
Such experimentation is not merely routine optimization of a known operative embodiment. For substantial portions of the claimed scope, the experimentation is required to determine in the first instance whether the selected compound or combination possesses the properties necessary to achieve the claimed functional result. The necessity for screening candidate members of a functionally defined class is directly relevant to the full-scope enablement inquiry under MPEP §§ 2164.01(a) and 2164.08 and Amgen.
Claim-specific application
Claim 1 is not enabled commensurate with its scope because it encompasses a functionally defined genus of topical RORC-product inhibitors without restriction to RORCi, the particular chemical species demonstrated in the working example, or another structurally defined class. The disclosure does not provide a predictive relationship permitting the skilled artisan to determine, without substantial empirical testing, which members of that genus will possess appropriate potency, cutaneous delivery, target engagement, and activity sufficient to inhibit development of the recited p53-mutated keratinocyte-derived malignancy.
Claim 5 likewise encompasses the unrestricted RORC-product-inhibitor genus. Although the RORCi experiment demonstrates reduction of mutant-p53 keratinocyte clonal expansion under the particular disclosed conditions, the specification does not establish that structurally and pharmacologically different RORC inhibitors will predictably inhibit keratinocyte genotoxicity, epidermal proliferation and dedifferentiation, and/or mutant-p53 clonal expansion when administered topically.
Claim 6 presents an additional enablement deficiency because it requires inhibition of actinic keratosis and squamous-cell carcinoma. The working example measures mutant-keratinocyte clonal expansion rather than actual AK or SCC formation, progression, regression, or prevention. In view of the acknowledged complexity of topical delivery to diseased skin and the limited state of the art concerning drug disposition in AK and cancerous skin, the disclosed RORCi result does not reasonably enable the full therapeutic scope of claim 6 across the entire RORC-inhibitor genus.
Claim 7 limits the inhibitor to an RORγ inhibitor, RORγt inhibitor, or an inhibitor of both. That limitation does not cure the deficiency because those categories remain functional pharmacological classes encompassing chemically diverse compounds. The objective evidence demonstrates materially different potencies and in-vivo behavior among compounds within those classes.
Claims 9–12 present an even greater enablement concern because each requires multiple inhibitors or inhibitor types while no working multi-inhibitor embodiment is disclosed. The skilled artisan would be required to determine empirically which compounds can be combined, appropriate relative concentrations, formulation compatibility, cutaneous delivery, and whether the resulting combination provides the required biological effect. The specification does not disclose a relationship by which these results can reasonably be predicted.
Claims 13 and 14 respectively require twice-daily and once-daily administration. The additional dosing limitations are adequately described in the specification, but they do not cure the underlying enablement deficiency of claim 5 because the identity, dose, topical availability, and efficacy of the broadly claimed RORC inhibitors remain to be determined experimentally.
Claims 15 and 16 respectively limit the formulation and recite approximately 1% inhibitor. The specification provides adequate guidance for the recited dosage forms and specifically demonstrates a 1% RORCi formulation. Nevertheless, the nominal concentration of a topical preparation does not establish equivalent cutaneous exposure among chemically different RORC inhibitors. The art establishes that skin penetration depends upon the physicochemical characteristics of the particular compound and the selected formulation. Accordingly, these limitations do not render the full underlying functional genus enabled.
Claim 17 additionally requires application of an anti-skin-cancer agent selected from sunscreen, antioxidants, anti-aging agents, and anti-inflammatory agents. The specification describes these classes of additional agents, but does not provide a working example establishing the claimed carcinogenesis-related effect when any such agent is used with an RORC inhibitor. More importantly, the added agent does not materially narrow the RORC-inhibitor genus responsible for the underlying enablement deficiency of claim 5.
Conclusion
Upon consideration of the Wands factors as a whole, the high level of ordinary skill and the specification's general guidance concerning candidate inhibitors, concentrations, dosage forms, and administration schedules weigh in favor of enablement. However, those considerations are outweighed by the breadth of the functionally defined inhibitor genera, the unpredictable nature of receptor pharmacology and topical drug delivery, objective evidence demonstrating materially different activities among RORγ/RORγt inhibitors, the compound-dependent nature of skin penetration, the limited state of knowledge concerning topical drug disposition in AK and cancerous skin, the single relevant working RORCi example, the absence of any multi-inhibitor working example, and the substantial empirical experimentation required to identify additional compounds and combinations capable of achieving the claimed biological endpoints.
Accordingly, the specification does not reasonably enable one of ordinary skill in the art to practice the full scope of claims 1, 5–7, and 9–17 without undue experimentation. The scope of enablement provided by the disclosure therefore is not commensurate with the scope of protection sought by these claims.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 18 is/are rejected under 35 U.S.C. § 102(a)(1) as anticipated by Chen et al., U.S. Publication No. 2018/0085348 (“Chen”).
Claim 18 recites a composition comprising at least one topical inhibitor of an RORC product selected from an RORγ inhibitor, an RORγt inhibitor, or an inhibitor that inhibits both RORγ and RORγt, together with a pharmaceutically acceptable excipient.
Chen expressly discloses pharmaceutical compositions prepared by admixing “one or more RORγ inhibitors, such as SR2211 and/or XY011,” with a pharmaceutically acceptable carrier, excipient, or diluent. Chen further identifies standard pharmaceutical carriers and excipients. See Chen, Pharmaceutical Compositions, full-text ll. 1675–1680. Chen further teaches that the disclosed compounds and compositions may be formulated for topical administration and specifically identifies creams, ointments, sprays, lotions, and patches as typical topical formulations. See Chen, ll. 1720–1724. Chen also expressly identifies SR2211 and XY011 as small-molecule inhibitors of RORγ. See Chen, ll. 1801–1803.
Accordingly, Chen discloses, in a single reference, (1) an RORγ inhibitor, which satisfies one of the alternatives expressly recited in claim 18; (2) formulation of that inhibitor for topical administration; and (3) a pharmaceutically acceptable excipient or carrier. Anticipation does not require Chen to disclose every alternative appearing in the Markush-type limitation of claim 18. Where a claim embraces alternative structures or compositions, disclosure of one subject matter falling within the claimed alternatives is sufficient.
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.
Claims 1, 5–8, 10–11, 13–15, and 17 is/are rejected under 35 U.S.C. § 103 as being unpatentable over Cozzi et al., U.S. Patent Publication No. 2014/0242012 (“Cozzi”), in view of Chen et al., U.S. Patent Publication No. 2018/0085348 (“Chen”), and further in view of Slominski et al. (“Slominski”).
Claim 1
Claim 1 recites repetitive topical application of an inhibitor of an RORC product to inhibit development of a keratinocyte-derived malignancy characterized by p53 mutation.
Cozzi expressly establishes the claimed UV/p53/keratinocyte disease context. Cozzi states that p53 mutations are particularly common in skin cancer and are an important early event in skin carcinogenesis; chronic UV exposure produces “p53 patches” that are clonal outgrowths of keratinocytes expressing mutant p53; such mutant p53 patches can progress to actinic keratosis and ultimately non-melanoma skin cancer; and UV-mutated keratinocytes constitute a prerequisite for development of most non-melanoma skin cancers. See Cozzi, WO counterpart full-text ll. 108–116; U.S. counterpart ll. 147–154.
Cozzi further teaches topical field-directed treatment of UV-damaged skin to prevent formation of skin lesions, remove UVB-induced p53-positive patches, reduce mutant p53 keratinocyte patches, remove subclinical precancerous cells, and prevent skin-cancer formation. See ll. 193–208. Particularly, Cozzi teaches topical treatment that reduces mutant-p53 patches and mutated keratinocytes and thereby prevents cancer-cell formation. Id., ll. 197, 201–207.
Cozzi differs from claim 1 principally in using ingenol mebutate rather than an RORC inhibitor as the topical active agent.
Chen supplies the missing RORC-targeting active. Chen identifies RORγ inhibition as an anticancer therapeutic approach, identifies SR2211 and XY011 as RORγ inhibitors, and expressly lists skin cancer among cancers suitable for treatment using its RORγ-inhibitor compositions. See Chen, l. 1668 and ll. 1801–1803. Chen further teaches that pharmaceutical compositions containing one or more RORγ inhibitors are administered at therapeutically effective doses and that the RORγ compounds may be formulated for topical administration. See Chen, ll. 1710–1716 and 1720–1724.
Slominski provides the biological bridge between Chen's RORγ anticancer teaching and Cozzi's keratinocyte-based cutaneous treatment. Slominski reports that RORγ is expressed in human skin, including epidermal keratinocytes; demonstrates antagonism/inverse agonism of RORγ; demonstrates inhibition of ROR-responsive reporter activity in keratinocytes; and expressly concludes that the ROR signaling pathway provides possibilities for local skin regulation. See Abstract at p. 2775 and Results, “Expression of RORs in skin.”
One of ordinary skill in the art therefore would have had reason to employ a topically deliverable RORγ inhibitor taught by Chen in the field-directed skin-treatment method taught by Cozzi. The motivation is supplied by the references themselves: Cozzi identifies UV-induced mutant-p53 keratinocyte clones as the precursor population to be reduced to prevent cutaneous malignancy; Chen identifies RORγ inhibition as an anticancer strategy applicable to skin cancer and expressly permits topical administration; and Slominski establishes that RORγ is present and pharmacologically regulatable in human epidermal keratinocytes. The proposed modification therefore places a known RORγ-targeted anticancer agent at a tissue in which the RORγ target was known to be expressed, for the same general objective of inhibiting progression of cutaneous malignant cells.
A person of ordinary skill also would have had a reasonable expectation of success because the art did not merely speculate that RORγ might be present in skin: Slominski experimentally demonstrated RORγ expression and pharmacological modulation in keratinocytes, while Chen demonstrated pharmacological inhibition of RORγ-associated cancer-cell growth and expressly taught topical pharmaceutical formulations. The expectation required by § 103 is reasonable predictability of achieving the intended RORC inhibition and anticancer effect, not certainty that every UV-induced lesion would be prevented.
Claim 5
Claim 5 is directed to repetitively applying a topical RORC inhibitor in sufficient concentration and duration to inhibit at least one of keratinocyte genotoxicity, epidermal proliferation/dedifferentiation, or mutant-p53 keratinocyte clonal expansion.
Cozzi directly teaches the UV-induced endpoints. Chronic UV exposure causes mutant-p53 keratinocyte clonal expansion, DNA damage, epidermal changes and progression to AK/SCC. See Cozzi, ll. 147–154. Cozzi's topical treatment reduces mutant-p53 keratinocyte patches and mutated keratinocytes, reverses UV-associated epidermal thickening, reduces subsequent lesions, and prevents cancer-cell formation. See Cozzi, ll. 197–205. Because claim 5 requires inhibition of “at least one” of the listed endpoints, Cozzi's express reduction of mutant-p53 keratinocyte clonal patches is sufficient to establish the claimed biological endpoint.
For the reasons set forth for claim 1, Chen would have suggested using a topical RORγ inhibitor as the active agent and Slominski supplies a reasonable expectation that RORγ can be locally pharmacologically modulated in epidermal keratinocytes. The substitution would have amounted to use of a known topically administrable anticancer RORγ inhibitor in a known topical field-treatment method directed to the same pathological skin tissue and precancer/cancer objective.
Claim 6
Claim 6 recites inhibiting actinic keratosis and squamous-cell carcinoma by repetitive topical RORC inhibition.
Cozzi expressly identifies actinic keratosis and SCC as UVB-induced lesions and teaches topical treatment of UV-damaged skin evolving into subclinical AK, AK, and cancer cells, as well as topical treatment of SCC tumors. See Cozzi, ll. 152–154 and 208, 213–217. Modification to employ Chen's topical RORγ inhibitor would have been obvious for the reasons stated for claims 1 and 5.
Claim 7
Claim 7 limits the RORC inhibitor to an RORγ inhibitor, an RORγt inhibitor, or an inhibitor of both isoforms.
Chen expressly teaches RORγ inhibitors, including SR2211 and XY011. See Chen, ll. 1801–1803. Because RORγ inhibitor is one of the alternatives recited in claim 7, no additional selection is required to meet the limitation.
Claim 8
Claim 8 selects the inhibitor from ML209, RORCi, digoxin, ursolic acid, SR1001, SR2211, TMP778, VPR-66, GSK805, and GSK2981278.
Chen expressly discloses SR2211 as an RORγ inhibitor and further identifies TMP778 and GSK805 among known RORγ inhibitors. See Chen, ll. 1801 and 1805. Disclosure of any one member of the closed alternatives recited by claim 8 meets the additional claim limitation; Chen supplies at least three.
Claim 10
Claim 10 requires administration to the skin of two or more RORγ inhibitors.
Chen repeatedly teaches pharmaceutical compositions and methods containing “one or more RORγ inhibitors, such as SR2211 and/or XY011.” See Chen, ll. 1677–1680 and 1713–1719. The phrase “SR2211 and/or XY011” expressly encompasses administration of both SR2211 and XY011, and both are identified as RORγ inhibitors. Chen further teaches topical administration. See Chen, ll. 1720–1724. Thus, in combination with Cozzi's UV-damaged-skin treatment, the additional limitation of claim 10 would have been obvious.
Claim 11
Claim 11 requires administration of two or more RORγt inhibitors to the skin.
Chen provides particularly relevant functional evidence. Chen identifies SR2211 and XY011 as RORγ inhibitors and expressly explains that SR2211 and XY011, together with other RORγ inhibitors including TMP778 and GSK805, “were identified based on their activity to inhibit RORγt function” in immune cells. See Chen, ll. 1801 and 1805–1806. Chen's disclosure of one or more RORγ inhibitors, “SR2211 and/or XY011,” therefore encompasses two distinct compounds each having demonstrated RORγt-inhibitory function. Chen, ll. 1677–1680, 1713–1719. Topical administration is taught at ll. 1722–1724.
Claims 13 and 14
Claims 13 and 14 respectively require twice-daily and once-daily administration of the RORC inhibitor.
Chen expressly states that the daily dose may be administered once per day or divided into multiple doses, expressly including twice per day. See Chen, l. 1764. Because Chen separately teaches topical administration of its RORγ compositions, selection of either expressly disclosed dosing frequency for the topical RORγ treatment would have involved use of Chen's disclosed dosing regimen for Chen's disclosed active agent, with a reasonable expectation of obtaining continued target inhibition.
Claim 15
Claim 15 requires formulation in a gel, ointment, cream, foam, spray, or solution.
Chen expressly identifies creams, ointments and sprays as typical topical formulations. See Chen, ll. 1722–1724. Cozzi additionally employs a topical gel. See Cozzi, ll. 201–208, 213–215. Thus, several expressly recited claim-15 alternatives were conventional and expressly taught.
Claim 17
Claim 17 further requires applying an anti-skin-cancer agent selected from sunscreen, antioxidants, anti-aging agents, and anti-inflammatory agents.
Cozzi expressly teaches that sunscreen treatment which reduces p53 patches also reduces the number of skin cancers that subsequently develop. See Cozzi, ll. 147–153, particularly l. 151. A person of ordinary skill seeking to inhibit UV-induced cutaneous carcinogenesis would have had reason to use the RORγ-targeted topical treatment together with sunscreen because the two known interventions address complementary components of the same recognized UV-carcinogenesis process: sunscreen reduces continuing UV-driven formation/expansion of mutant-p53 patches, while the RORγ inhibitor acts locally on the RORC pathway in skin. Each component would have been expected to retain its known function, yielding the predictable combined objective of reducing UV-driven carcinogenic progression.
Claim 16 is rejected under 35 U.S.C. § 103 as being unpatentable over Cozzi in view of Chen and Slominski, as applied above to claim 15, and further in view of Smith et al. (“Smith”).
Claim 16 requires that the topical RORC-inhibitor composition comprise about 1% inhibitor.
Smith expressly developed RORγ/RORγt small-molecule inhibitors for topical skin administration. Smith explains that local inhibition of RORγ/RORγt with small molecules is advantageous in accessible skin tissue and describes a potent small-molecule inhibitor of RORγ/RORγt for topical treatment. See Smith, Introduction, ll. 206–215. Smith identifies GSK2981278, GSK3038548 and GSK3038549 as RORγ inverse agonists; all three reduced RORγ activity, and all three inhibited RORγt transactivation. See Smith, Results, ll. 260–267.
Most importantly for claim 16, Smith expressly reports topical administration of the RORγ/RORγt inhibitor at 1%: mice were treated topically with compound in a 60% ethanol/40% water solution at 1% or 0.1%, or in ointment at 1%. See Smith, Materials and Methods, ll. 244–246.
It therefore would have been obvious to employ the expressly taught approximately 1% concentration when formulating the RORC inhibitor of the combined Cozzi/Chen treatment. This is not a rejection based solely on “routine optimization”; Smith supplies the precise claimed concentration for a topically administered RORγ/RORγt inhibitor in skin.
Claim 9 is rejected under 35 U.S.C. § 103 as being unpatentable over Cozzi in view of Chen and Slominski, as applied to claim 7, and further in view of Smith.
Claim 9 requires that two or more inhibitors, each of which inhibits both RORγ and RORγt, be administered to the skin.
Chen expressly contemplates more than one RORγ inhibitor in the same pharmaceutical treatment or composition, repeatedly describing “one or more RORγ inhibitors, such as SR2211 and/or XY011.” See Chen, ll. 1677–1680 and 1710–1719. The “and/or” formulation expressly encompasses use of SR2211 and XY011 together.
Chen further supplies evidence that each of those agents has the dual functional activity required by claim 9. Chen identifies both SR2211 and XY011 as small-molecule RORγ inhibitors, ll. 1801–1803, and expressly states that SR2211 and XY011 were identified based on their activity to inhibit RORγt function. See Chen, ll. 1805–1806. Thus, the same reference identifies two distinct compounds having both RORγ-inhibitory identity and RORγt-inhibitory function and expressly contemplates their use as “SR2211 and/or XY011.”
Smith independently confirms that dual RORγ/RORγt pharmacology was an established property of this class rather than an Applicant-discovered phenomenon. Smith explains that RORγt and RORγ share the same DNA- and ligand-binding domains and expressly proposes local inhibition of “RORγ/RORγt” in skin. See Smith, ll. 211–215. Smith experimentally evaluated three different compounds—GSK2981278, GSK3038548 and GSK3038549—and reports that all three were RORγ inverse agonists while all three also inhibited RORγt transactivation. See Smith, ll. 265–267.
Accordingly, before the effective filing date, the art taught (1) multiple chemically distinct compounds each having RORγ/RORγt inhibitory activity; (2) use of more than one RORγ inhibitor, expressly including SR2211 and/or XY011; and (3) topical/local RORγ/RORγt inhibition in skin.
A person of ordinary skill therefore would have had reason to administer the two Chen inhibitors together in the topical treatment because Chen itself contemplates the combination and because both agents operate through the same established RORC target system. Each inhibitor would have been expected to continue performing its known RORγ/RORγt-inhibitory function. No synergistic effect between the two agents is required by claim 9.
Claim 12 is rejected under 35 U.S.C. § 103 as being unpatentable over Cozzi in view of Chen and Slominski, as applied to claim 7, and further in view of Karstens et al., U.S. Patent Publication No. 2014/0038942 A1 (“Karstens”), and Smith.
Claim 12 requires administration to the skin of two or more types of RORC inhibitor selected from (1) an RORγ inhibitor, (2) an RORγt inhibitor, and (3) an inhibitor that inhibits both RORγ and RORγt. Thus, unlike claim 9, claim 12 requires representatives of different inhibitor categories.
Chen supplies the RORγ-inhibitor component. As explained above, Chen teaches RORγ inhibitors including SR2211 and XY011, pharmaceutical compositions containing such inhibitors, topical administration, and treatment of cancer including skin cancer. See Chen, ll. 1668, 1677–1680, 1720–1724 and 1801–1805.
Karstens supplies an independently developed RORγt-inhibitor class. Karstens, published February 6, 2014, is expressly directed to “RORgammaT inhibitors.” See cover, p. 1, ll. 0–19. Karstens states that the compounds are useful for treatment of RORγt-mediated diseases and expressly includes psoriasis. See ¶¶ [0255]–[0257], p. 12, ll. 1025–1037. Karstens further teaches topical, including transdermal, administration of its RORγt inhibitors. See ¶[0258], p. 12, ll. 1038–1047.
Karstens also expressly contemplates administering its RORγt inhibitor “in a combination of therapeutic agents.” See ¶[0259], pp. 12–13, ll. 1051–1056. More specifically, Karstens defines coadministration as administration of two agents concomitantly, sequentially, or as a fixed-dose combination. See ¶[0279], p. 14, ll. 1218–1226. Its Combination Therapy section further teaches administration of at least one RORγt-inhibiting Formula I compound and at least one other pharmaceutically active agent, together or separately, in amounts and relative timing selected to achieve a desired combined therapeutic effect. See ¶[0284], p. 14, ll. 1253–1270.
Smith supplies the mechanistic reason that would have led the skilled artisan to select another RORC inhibitor, rather than an unrelated active agent, as the second component. Smith teaches that RORγt and RORγ share the same DNA- and ligand-binding domains and specifically characterizes local inhibition of “RORγ/RORγt” in skin as a therapeutic opportunity. See Smith, ll. 211–215. Smith's experiments further establish that distinct small molecules can inhibit both RORγ and RORγt. See Smith, ll. 265–267.
The difference between the combined prior art and claim 12 is therefore the selection, as Karstens' additional therapeutic agent, of Chen's RORγ inhibitor to accompany Karstens' RORγt inhibitor in Cozzi's topical UV-damaged-skin treatment.
One of ordinary skill would have had reason to make that selection because: Chen teaches that RORγ inhibition is an anticancer therapeutic strategy applicable to skin cancer and permits topical delivery; Karstens teaches topical RORγt inhibition and expressly encourages combination therapy; Smith establishes that RORγ and RORγt are closely related isoforms sharing the relevant ligand-binding architecture and expressly teaches local RORγ/RORγt inhibition in skin; and Slominski establishes RORγ as an accessible pharmacological target in human epidermal keratinocytes. These teachings would have made concurrent local inhibition of the two recognized RORC products a rational way of broadening RORC-pathway inhibition in the treated skin.
There also would have been a reasonable expectation of success. Both inhibitor classes were independently known, both targets were known components of the same RORC system, both classes were taught as pharmacologically inhibitable, topical administration was expressly taught for both Chen's RORγ compounds and Karstens' RORγt compounds, and Smith specifically demonstrated the feasibility of local RORγ/RORγt pharmacological inhibition in skin. The proposed combination therefore does not require a new mechanism to arise from the combination; each known inhibitor would merely be expected to inhibit its known RORC target in the same locally treated tissue.
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/DEBORAH D CARR/Primary Examiner, Art Unit 1691
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