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 Status
Claims 1-71, 74-76 and 91 are cancelled. Claims 72, 73 and 77-90 are pending and under examination. Applicant only amends claim 80 to indicate that the subject is administered with a composition for injection to a tumor and also with a composition for topical administration and also changes “day 8” to “day 5” and “up to 4” to “up to 2”, where claim 80 depends on claim 72.
Rejection Withdrawn
The rejection under USC 102 (was actually 103 obviousness) over Kottmann and Singh is withdrawn as the rejections over Skvara and over Skvara and Au would teach the claimed formulation with a reasonable expectation of success.
As this rejection is withdrawn, applicant’s arguments to this rejection are moot.
Objection to New Drawings
The new submitted drawings from 12/22/2025 are a research paper and not drawings/figures. This is objected to for not being proper drawings. Additionally, by submitting this paper as drawings, this would add new matter to the disclosure as drawings are considered part of applicant’s disclosure.
The amendment/drawings filed 12/22/2025 are objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: A research paper being submitted as drawings, which are considered part of the disclosure.
Applicant is required to cancel the new matter in the reply to this Office Action.
New Rejections – As Necessitated by New Amendment to claim 80
Claim Rejections - 35 USC § 112- New Matter
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.
Claim 80 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Applicant amended “day 8” to “day 5” for causation of undetectability and amended administration up to 4 more days to “up to 2 more days”. Neither of these changes in days appear to be supported by applicant’s originally filed specification and originally filed claims. Day 8 undetectability/not recognizable had been previously supported as well as continued for four more days in the originally filed specification (last paragraph of page 22 of applicant specification). It is not observed where applicant has support to change day 8 to day 5 and 4 to 2 in this or other parts of applicant’s originally filed disclosure. Thus, this adds new matter to applicant’s disclosure.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 80 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 80 recites “the subject is administered with a composition for injection to tumor and also with a composition for topical administration”, which makes it unclear if “a composition” in each of these recitations are new compositions that may have other ingredients or if “a composition for injection to tumor” is supposed to be the composition in claim 72. Additionally, it is unclear if “a composition for topical administration” is supposed to also contain the “molecule that is a selective inhibitor of hedgehog/smoothened signaling” since a composition for topical administration is not part of claim 72. One suggestion is that applicant recite this portion as “the subject is administered the composition for injection to tumor and also with a composition for topical administration, wherein the composition for topical administration comprises a molecule that selectively molecule that is a selective inhibitor of hedgehog/smoothened signaling, “ For the purpose of compact prosecution, the examiner will consider the “a composition for injection to tumor” as being a composition introduced by claim 72 and the composition for topical administration will be considered as any composition that the prior art would teach that is topically administered.
Maintained Rejections
Claim Rejections – 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(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.
Scope of Enablement for Claiming Molecules By Function(s) Rather Than Providing the Structure(s) Needed for the Functions
Factors to consider for enablement are:
(A) The breadth of the claims;
(B) The nature of the invention;
I The state of the prior art;
(D) The level of one of ordinary skill;
I The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
Claims 72-73, 77, and 79-90 are 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 cyclopamine, jervine and Veratrum steroidal alkaloids, does not reasonably provide enablement for all molecules inhibiting Hedgehog/Smoothened signaling in claim 72 or in the case of claim 82 non-cyclopamine molecule that selectively inhibits the transcriptional effects of Hedgehog/Smoothened signaling and causes, in comparison to cyclopamine, less inhibition or no inhibition of a Smoothened-mediated non-transcriptional effect that supports blood vessel maintenance and/or angiogenesis. Non-cyclopamine provides what it is not without providing a certain structure. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use all the molecules with functions dictated by the claims of the invention commensurate in scope with these claims. Applicant’s claims provide for molecules inhibiting Hedgehog/Smoothened signaling in claim 72 or in the case of claim 82 non-cyclopamine molecule that selectively inhibits the transcriptional effects of Hedgehog/Smoothened signaling and causes, in comparison to cyclopamine, less inhibition or no inhibition of a Smoothened-mediated non-transcriptional effect that supports blood vessel maintenance and/or angiogenesis. These are molecules of no particular structure that are defined by the functions they offer. The molecules may be antibodies, polynucleotides, oligonucleotides, peptides, small organic molecules or possibly other types of molecules.
Fan et al (Cell & Bioscience, 2021, volume 11, pages 1-11) teaches that a potent antagonist of smoothened in hedgehog signaling was identified (abstract). The synthesis of the compound is provided in figure 4 of Fan. This compound that was made after the filing date of applicant’s invention, and thus, making the compound in Fan was not enabled at the time of applicant’s invention. Teng et al (American Journal of Student Research, June 2024, volume 2, pages 1-8) provides advances in targeting SMO to inhibit the sHH signaling pathway for tumor treatment (abstract). Teng teaches that SMO is an attractive target for drug development (page 3, Targeting SMO for Cancer Treatment). Teng teaches different compounds that are SMO inhibitors where not all of them share the similar structure of cyclopamine (see figure 2 of Teng). Teng provides for compounds that are non-cyclopamine derivatives-based SMO inhibitors that are structurally completely different from cyclopamine and its derivatives (page 5 of Teng). Thus, there is structural diversity in the compounds that can inhibit Smoothened and the hedgehog pathway with applicant only providing cyclopamine and jervine (2 Veratrum steroidal alkaloid SMO inhibitors) in their disclosure. This diversity makes it difficult to enable any particular compound/molecule as it must be made/isolated and then tested for such activity. As the claims can also cover antibody antagonists as molecules, Kerry (rapid novor, Antagonist Antibodies: Opportunities and Obstacles, 2024, https://www.rapidnovor.com/antagonistic-antibodies-opportunities-obstacles/) teaches that there are many obstacles to discovery and development of new antagonistic antibodies. Kerry teaches obstacles that include specificity and affinity, target antigen conformation, biological activity confirmation, immune response modulation, engineering considerations, epitope selection and the in vivo behavior of the antibody. Thus, there are many considerations and difficulties in creating new antagonist antibodies and verifying their function. Applicant’s own arguments on page 26-27 note that structurally diverse compounds capable of inhibiting Hh/Smo signaling sometimes have more toxicity and preclude treatment from reaching beneficial results toward no recurrence of tumors. Thus, applicant cannot use any such compound. The claim is not specific to a species or even a specific subgenre of compounds that are close to structure to which applicant has results for (cyclopamine).
Applicant provides for use of cyclopamine in its working examples. Applicant provides for jervine as a related compound and provides the structure of cyclopamine (a Veratrum steroidal alkaloid). These are the most defined structures presented in applicant’s specification. There is no testing of a compound other than cyclopamine. Applicant mentions blocking anti-Hh antibodies with citing a reference which might disclose particular species of antibodies, but does not provide for certain structures with defined sequences of antibodies that would have such inhibiting functions and be useful to applicant’s invention. Further, Applicant does not dictate species of non-cyclopamine compounds in their disclosure that would function in contrast to cyclopamine in regards to the limitation with blood vessel maintenance and/or angiogenesis.
One of skill in the art is a medical doctor or research scientist in cancer biology.
As the prior art recognizes compounds that were only enabled after applicant’s effective filing date, variations in SMO inhibitor structure that would be significantly different from the small molecule compounds cyclopamine and jervine and obstacles in making and testing antagonistic antibodies while applicant’s disclosure only provides for few species of compounds and tests only cyclopamine, one of skill in the art would have to conduct undue experimentation to make, identify and test all the compounds/antibodies/other molecules for these functionalities. As the area of cancer therapeutics is often unpredictable, one of skill in the art is high and the genus claimed by applicant is extensively large to the molecules it can cover, there would need to be undue experimentation by one of skill in the art to establish enablement for making and using the breadth of such molecules. Currently, the claimed genre encompass potentially millions of possible compounds/antibodies/other molecules with various structures and binding sites. Thus, the whole genus of such molecules defined by functionality is not enabled by applicant. However, cyclopamine, jervine or Veratrum steroidal alkaloids with those claimed functions (inhibiting Hh/Smo signaling, etc) are enabled due to sharing of common structures that are known to provide such functionalities.
In the added case of “in comparison to cyclopamine, less or no inhibition of a Smoothened mediated non-transcriptional effect that supports blood vessel maintenance and/or angiogenesis” as being an added functionality of the non-cyclopamine molecule in claim 82, unless jervine is that compound that performs this function, there does not appear to be another compound and this would also lack enablement for not providing a structure that would both inhibit the Hh/Smo signaling pathway and perform this function. Again, non-cyclopamine does not define a structure that can be linked to the function, other than the molecule not being cyclopamine.
Note that MPEP 2164.01 “In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR.” This case defines a molecule without structure by functions of that molecule (e.g. inhibiting Hh/Smo signaling). Also in MPEP 2164.01 “The Court clarified that the specification does not always need to “describe with particularity how to make and use every single embodiment within a claimed class.” Id. At 610-11. However, “[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable.” Id.”
Response to Arguments
Applicant argues that the specification does teach all the molecules inhibiting Hh/Smo signaling are suitable for treatment of a tumor bearing human and believes the rejection to be in error. The examiner disagrees. It is further noted the applicant indicates “selectively inhibits” indicating that these are selective inhibitors and applicant notes that vitamin D3 is a molecule that would not be selective and cause unintended side effects (see top of applicant arguments from 12/22/2025, page 7), however, this does not show all the compounds that would be covered by this functional language in the claim. In claim 82, the inhibitor is further defined by what it is not as being non-cyclopamine (molecule that isn’t cyclopamine) and that the molecule “selectively inhibits transcriptional effects of Hedgehog/Smoothened signaling” with less or no inhibition of non-transcriptional effects that support blood vessel maintenance and/or angiogenesis in comparison to cyclopamine (molecule does not function exactly as cyclopamine in this manner). It is appreciated that the applicant desires to claim this entire genus by its functional (able to treat tumors in the fashion claimed) and mechanistic characteristics (ability to selectively inhibit Hh/Smo signaling, or ability to block transcriptional effects, but not certain non-transcriptional effects), but it remains that the specification provides limited species of compounds with defined structures that may be capable of this with cyclopamine being mentioned over 180 times and exemplified in the specification and jervine mentioned 3 times (paragraph 7 of specification), but not used in examples. The only working examples involves cyclopamine itself. Applicant mentions antibodies capable of providing selective inhibition of Hh/Smo signaling, but does not provide all the relevant structures/sequences for such antibodies that would be capable of this. Thus, this might support the use of Veratrum steroidal alkaloids to have such expected functionality based on cyclopamine (a compound that is a veratrum steroidal alkaloid), although not all of these may be “selective” or as effective for this method. Applicant’s claims remain broad enough to come multitudes of other possible type of compounds and molecules (e.g. protein inhibitors, peptide inhibitors, antibodies, many other structures of chemical compounds). It is important to note that ““[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable.” Id.” (see MPEP 2164.01). If applicant mentions in words or structures any other particular species of compounds in the originally filed disclosure, then applicant may provide these in a Markush group within the claims. Besides the priority documents, it does not appear that applicant has “incorporated by reference”, the references it cites within the specification (see 37 CFR § 1.57 in MPEP 608.01(p)) where only incorporation by reference of former US Patents and US Patent application publications can be used for “essential matter” (e.g. the inhibitors). Changes to the specification at this point may be viewed as incorporating new matter into the disclosure.
Applicant argues that the limitation of “a molecule that selectively inhibits Hedgehog/Smoothened signaling” is a class specific term that recognizes a class of molecules that would be structurally different compared to those that would not have this function. Again, although structures like that of cyclopamine or jervine (veratrum steroidal alkaloids that inhibit Hh/Smo signaling) are provided based on these being known compounds, this does not support all the other structures of molecules that are able to perform these functions and have these effects. Note “molecules” may not only cover such small organic compounds such as those that are veratrum steroidal alkaloids, but proteins of various sequences, peptides of various sequences, and, of course, various other small organics with varying structures. In applicant’s claim 77, it is provided that the molecule binds to smoothened protein to cause inhibition, but applicant has not provided enough diverse ways of molecules binding to smoothened and in what way they would bind with which possible structures would be important for that binding to Smoothened. Applicant does not provide enough subgroups or species thereof within its specification along with functional data for each to support enablement for this entire genus with a showing that each would reasonably have the selective inhibition and the ability to cause a reduction of tumor size until its disappearance. Applicant could consider limiting the independent claims to indicate “wherein the molecules that selectively inhibit Hedgehog/Smoothened signaling are veratrum steroidal alkaloids” (page 7 of specification provides for veratrum steroidal alkaloids), which are molecules from the extensive genus that have enablement. Note that under Amgen v. Sanofi (2023), such broad claims are invalid if the specification requires "undue experimentation" to identify the full scope of functional compounds, necessitating detailed structure-function data, not just a, "roadmap". It is appreciated that inhibition of this pathway has anti-tumor effects shown by certain compounds such as cyclopamine, but the issue remains that the full scope of the claim to all other various molecules provided only by function is not enabled since all such corresponding structures capable of these function are not provided.
Applicant argues starting on the bottom of page 7 of their response that a skilled person knows a drug molecule per se does not cause a particular therapeutic effect and it must be administered to cause a certain therapeutic effect. This does not replace the need for structural information (structure-function data) for a representative number of items in the genus, since the structures control the effects the molecule would provide to selectively inhibit the Hh/Smo pathway as well as to treat tumors.
From the page 8 until page 10, applicant argues what is known about inhibiting Hh/Smo signaling and its anti-cancer effects in the prior art. Certainly, this becomes an issue when considering the prior art as anti-tumor effects, but it does not replace the need for structure-function data for this large and potentially diverse genus of molecules that applicant even deems to include antibodies as well as organic compounds structurally different from cyclopamine or jervine.
On page 8 of applicant’s arguments, applicant argues that prior art lacked the ability to administer compounds in a manner to achieve the effect in the claim. This is one part of the issue as applicant only provides data for use of cyclopamine (a specific species), but no other compounds/molecules. Also, the results achieved are functional language and there would still be a need for structure-function for a number of such molecules to offer a representative number of different molecule structures capable of these functions. See MPEP 2164.01 “ The Court clarified that the specification does not always need to “describe with particularity how to make and use every single embodiment within a claimed class.” Id. at 610-11. However, “[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable.” Id.”. This section, again, notes Amgen Inc. et al v. Sanofi et al where “the Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR.” In this case, the parallel is that there is language claiming the molecule by function with limited structures presented in the disclosure (i.e. cyclopamine, a Veratrum steroidal alkaloid like jervine) that might be capable of performing such functions. It cannot be said that the prior art enables all the possible molecule structures that can exist in this genus capable of this function and applicant has not provided their own data to do so. Even if there are prior art papers to a few antibodies or other molecules capable of doing so, this does not necessarily enable the production of all antibody structures that could fall under this genus that will. The standard for enablement is to show one skilled in the art how to make and use the claimed invention, and thus, there is a deficiency in how to make and how to use all molecules for these functions besides the few that applicant has provided which happen to have particular structures.
From page 11 until the middle of page 12 of applicant’s arguments, applicant cites the specification regarding the showing of the signaling inhibition and anti-tumor effect of cyclopamine as well as indicating that prior art found in the specification (not incorporated by reference) provides for other inhibitors of Hh/Smo signaling. It is appreciated that some other prior art structures may be capable of such effects, but it still does not provide all the molecules this genus would encompass with the structure-function data needed to support enablement of the claim.
From the middle of page 12 to page 17 of applicant’s response, applicant argues that prior art has pointed out 4-5 other compounds (e.g. SANT-1, SAG, GDC-0449 and LDE-225 on page 15 of arguments) capable of selectively inhibiting Hh/Smo signaling with some mention of binding pockets and treating tumors/cancer while also pointing out the specification’s discussion on topics related to possible kinases affected by non-selective inhibitors and non-transcriptional effects. In regards to applicant’s mention of other compounds in the prior art, these are relatively few in number compared to the millions of molecules that might exist for this genus. In regards to recognized binding pockets, this was one concern that was made in Amgen Inc. et al v. Sanofi et al, since showing the binding pockets/binding site in the target protein does not provide structure to the molecules themselves that are supposed to bind it. In regards to discussing description for the functional language itself (e.g. non-transcriptional effects), the examiner has considered it, but it does not replace the need for the showing of sufficient structures (e.g. natural and synthetic compound structures, amino acid sequences, etc.) to enable the full genus of molecules being claimed by function language in the claims.
From the last paragraph of page 17 to page 20 of applicant’s response, applicant argues that one may readily make molecules of the claims based on the specification. Applicant indicates that the prior art shows diverse compound structures that selectively inhibit Hh/Smo signaling, and thus, methods of making compounds were generally known since such compounds were synthesized. Applicant then argues that IC50 values can be determined in a few days for any compound that is made. Applicant argues the specification and prior art provide enough information on such procedures to make compounds and compounds of applicant’s claims would be readily identifiable. Applicant argues that screening means are known and there would not have to be assumption of molecular structure. Essentially, applicant argues that one may just make compounds related to ones that were known in the prior art by similar means to make those compounds and then readily test for activity. This does not account for other molecules that could still have such function, but be significantly different structurally. Even making a new derivative of an old compound can require significant efforts to enable. There is no basis to make all the various molecules that can be encompassed by these genre defined by functional language. The art as cited by the examiner in this rejection provides for inhibitors made by teachings of Fan et al and teachings of Teng that were made well after applicant’s application filing. There was no enablement for making and using these compounds at the time of applicant’s invention. Furthermore, the examiner cited Kerry to demonstrate that making new antagonist antibodies (a molecule) was challenging to one of skill in the art. Thus, one would have to enable making a particular antibody in order to properly enable a claim that encompasses “molecules” that selectively inhibit Hh/Smo signaling and other functional features recited in the claims. Citing a prior art reference that shows making one or a few particular species of antibodies or compounds does not mean that one would be able to make other antibodies of different sequences and structures or chemical compounds of various other structures by those same teachings. The arts of chemistry and biotechnology are high skilled arts that require significant experimentation. Applicant’s claims would require undue experimentation by those of skill in the art in order to make and test all types of compounds that the genus defined by functional language indicates.
Lastly, applicant argues that claims 82 and 89 provide for a subgenus of the inhibitors covered in claim 72 based on additional functional language. Applicant feels these are reasonably enabled for similar reasoning they presented as methods to analyze blood vessels and angiogenesis are known. However, the rejection for scope of enablement also addresses these claims. Again, the language is additional functional language and applicant has a duty to enable it with the structure-function necessary to enable the various molecules in the genus that can carry out those functions. One of skill in the art would have to conduct undue experimentation to provide for the various molecules in this broad genus with these functional characteristics. Therefore, for the same reasons above, these claims remain rejected under scope of enablement.
Scope of Enablement – Without Recurrence
Claims 73, 80 and 84 are 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 treating a tumor in a subject where the tumor cells that involve Hh/Smo signaling, does not reasonably provide enablement for treating to the point where a tumor does not reoccur (note the claim does not provide a time for recurrence). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. In these claims, a tumor is treated by administration of the composition provided and leads to disappearance of the tumor without recurrence. “Without recurrence” refers to the tumor never occurring again after treatment.
American Cancer Society (Cancer.org, downloaded 2024, https://www.cancer.org/cancer/survivorship/long-term-health-concerns/recurrence/can-i-do-anything-to-prevent-cancer-recurrence.html) provides that there are ways to reduce risk of recurrence but the efforts cannot completely keep cancer from recurring. In addition, Oh et al (Cancers (Basel), 2021, volume 13, pages 1-11) teaches that cancer recurrence is a significant clinical issue in cancer treatment (abstract). Oh teaches in the introduction that cancer recurrence is present, and varies, by cancer type and is more than 70% for hepatocellular carcinoma (Introduction of Oh). Thus, there is a significant chance of recurrence after cancer treatment has been provided even with a treatment.
Applicant’s data and figures/drawings provide that tumors do shrink after the treatment. After a continued course of treatment, the tumors could shrink to undetectable levels where they could not be observed. Applicant does discuss a patient without recurrence for 3 ½ years (bottom of page 22 of specification). However, this is one patient (n=1) and nothing is stated for time point observations greater than 3 years after treatment to supposed disappearance. The data does not enable complete lack of recurrence (recurrence for the life of the patient). In order to provide support for no recurrence, one would have to monitor a larger number of patients with treatment as compared to those without over a course of many years. A significant amount of the patients would have to demonstrate tumor disappearance with no recurrence in this continuous monitoring to enable “without recurrence”. Additionally, different patients respond differently to treatments, and thus, it remains unknown whether this patient responded this way for other reasons or if it was based on the drug and its dosing alone.
One of skill in the art would be a doctor who specializes in cancer or a cancer biology scientist.
As the art does not provide for complete lack of recurrence of cancer and applicant’s specification has limited data on recurrence with one patient and a limited time frame, there would be undue experimentation by one of skill in the art to demonstrate that disappearance with no recurrence is actually occurring across a significant group of subjects. Thus, the applicant is enabled for treating as indicated by the claim and tumor shrinkage, but is not enabled for disappearance without recurrence. Applicant may provide data or further evidence that “without recurrence” would be possible in a number of patients with such a treatment targeting Hh/Smo signaling or amend the claim to remove the recitations of issue. Applicant may remove the recitation of “without recurrence” as a possible solution or provide objective evidence in a larger group of patients that would enable “without recurrence”.
Response to Applicant’s Arguments
Applicant argues that claims 73, 80 and 84 have proper enablement as support the disappearance without recurrence after 3 ½ years in one patient while it appears that other studies cannot show this effect with Hh/Smo inhibitors. However, tumor disappearance without recurrence is essentially seen as curing the tumor. The applicant’s specification shows a result for one patient. This one patient may represent an exceptional case. In order to show that it is truly enabled for tumor disappearance/eradiation without recurrence, a larger group of patients would need to be tested and observed long term. One of skill in the art would note studies to show there is no tumor recurrence (cured of the cancer) would need verification and statistical significance. The reference, Oh, that was cited in the rejection shows that even with a treatment there is a very high chance of recurrence. The one patient may offer hope, but it does not fully enable that tumor recurrence would not occur if the treatment is provided to other patients. The fact that other art as applicant discussed also has not shown no recurrence also makes it more necessary to have the proper verification and statistical significance. Providing statistics based on samples only from the same one patient is not convincing for no recurrence, since it still does not show the effect can happen across a group of different individuals. Thus, it would be undue experimentation for one of skill in the art to conduct such a study to verify this effect. If applicant has long-term data (at least 3 ½ years) with a larger group of patients and no recurrence is shown for those patients with statistical significance, then applicant may provide a declaration under rule 132 to provide this data.
Applicant argues that causing high efficiency apoptosis of cancer cells over a short period of time will cause their elimination without causing progenies with genetic-epigenetic changes making them resistant to apoptosis. Thus, applicant infers it would be understood that disappearance without recurrence is possible with such a treatment with selective Hh/Smo inhibitors inducing a high amount of apoptosis. Although something may be possible based on mechanism, it still requires a showing that it can be done for enablement especially to show no recurrence.
Applicant argues that the rejection is also in error because treatment can be readily provided by the method in the specification. However, just being able to carry out the treatment does not mean it will cause the same effect across a statistically significant number of patients (across a group). This requires sufficient experimentation to be performed. This remains what is in question.
Written Description
Claims 72, 73, 77, and 79-90 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 72 provides that the composition is comprised of “a molecule that selectively inhibits Hedgehog/Smoothened signaling”, but the specification only provides for cyclopamine, cyclopamine’s 4-ene-3-one derivative and jervine as compounds with this function. Claims 82 and 89 indicate that the molecule is non-cyclopamine and adds the functionality of “does not inhibit a Smoothened-mediated non-transcriptional effect that supports blood maintenance and/or angiogenesis”. This does not narrow to more particular compounds, but instead says the molecule is not cyclopamine and further provides an additional characteristic of its function. Cyclopamine and jervine have particular structures and would not give rise to all the possible molecules having such activities. Fan et al (Cell & Bioscience, 2021, volume 11, pages 1-11) teaches that a potent antagonist of smoothened in hedgehog signaling was identified (abstract). The synthesis of the compound is provided in figure 4 of Fan. This compound that was made after the filing date of applicant’s invention, and thus, making the compound in Fan was not described at the time of applicant’s invention. Nguyen et al (International Journal of Molecular Sciences, 2022, volume 23, pages 1-27, previously cited) provides for hedgehog pathway inhibitors as targeted cancer therapy (title and abstract). Besides cyclopamine, Nguyen mentions other distinct compounds that can serve as inhibitors or parts of the pathway to inhibit (section 5.1 and figure 6 “development of second generation SMO inhibitors”; section 5.2 “targeting downstream molecules of SMO”; figure 3- structures of selected SMO inhibitors). Thus, as the applicant’s description does not provide for such other compounds besides cyclopamine, one particular cyclopamine derivative and jervine, it does not provide sufficient description that would provide applicant ownership over all such other molecules or non-cyclopamine molecules that have these activities. Additionally, note that molecules can include many types of compounds including small organic molecules, inorganic molecules, proteins, antibodies, nucleic acids and others. There is not description over all such categories of what the molecule could be. Applicant does have description for cyclopamine, its 4-ene-3-one derivative and jervine, but not sufficient description to possess all other molecules that can have the activities that the claims indicate.
Response to Applicant’s Arguments
Applicant argues that there is written description for the genus as provided in the claim. As noted above the molecule in claim 72 is defined by its functional ability to selectively inhibit Hh/Smo signaling. The examiner disagrees. There is no structural formula or molecule that would have a noted formula present in claim 72. In claim 82, it has the limitation of claim 72 in regards to molecule plus it adds that the molecule is non-cyclopamine, and selectively inhibits transcriptional effects of Hh/Smo signaling with less or no inhibition of Smoothened-mediated non-transcriptional effect that supports blood vessel maintenance and/or angiogenesis. Again, claim 82 does not provide a structural formula or particular molecule that would have a noted formula. In the disclosure, Applicant provides for two specific species in its specification, cyclopamine and jervine, while using examples that test cyclopamine as the Hh/Smo inhibitor. However, the genus in the claim would encompass many other molecules. Applicant should note from MPEP 2163 that “A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”).” Also, “('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).")” (MPEP 2163 part 3). As these inhibitors can vary in chemical structures and or protein sequences (e.g. if antibodies) and applicant has only provided cyclopamine and jervine (and the subgenus of veratrum steroidal alkaloids) within its specification, it does not fully support the genus which encompasses many more types of molecules outside of veratrum steroidal alkaloids. For one, the applicant provides no description of an antibody of a particular sequence by its name or with SEQ IDs that is capable of these particular functions even though the specification in paragraph 7 mentions that antibodies (generally) can be made for selective inhibition of Hh/Smo signaling. This would normally require a showing key amino acid sequence(s) that allow the binding to have the inhibition occur. The specification does not provide such descriptions. In regards to other chemical compounds making compounds more selective than jervine or cyclopamine would take description of compounds structures that could accomplish such an improvement. Describing general modifications to make derivatives as in paragraph 58 of applicant’s specification (as PGPub) does not describe particular chemical groups or particular types of derivations to the compounds. Even with that said, such a derivative would still be in the subgroup with cyclopamine and not any other subgroups within the full genus of inhibitors as in the claims. Paragraph 88 of applicant’s specification also mentions the ability to alter structures including those not related to cyclopamine, but does not describe what those alterations would be. Applicant claims that the compounds are mentioned in the reference citations, but these are not incorporated by reference and applicant has not named such compounds in their own specification. Anyhow, incorporating non-patent literature by reference would only be for non-essential matter and not essential matter such as the compounds. Thus, the applicant does not provide ownership of these genus of molecules claimed by functions. There is support for cyclopamine and jervine, which are veratrum steroidal alkaloids. Applicant may use these compounds in the claims or recite “veratrum steroidal alkaloid” as the molecule.
Applicant provides for how the specification describes therapeutic effects, functions, general abilities to modify compounds, conventional pharmacokinetics/pharmacodynamics, and support for non-cyclopamine, but does not provide anything about other particular compound structures that would be capable of the selective inhibition of Hh/Smo signaling. It remains there are not a sufficient number of molecule species for applicant to claim the genre described by functions. Applicant’s claims attempt to claim more than they actually owned at the time of filing by way of reciting broad genre of “molecules” defined by function(s) while their description has few actual species of compounds that are within one specific subgenre (Veratrum steroidal alkaloids). This does not satisfy the written description requirement.
Therefore, this rejection is maintained.
Claim Rejections – 35 USC § 102
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(s) 72, 77-79 and 81 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tas US 20100048725.
Where verbs are presented in past tense with -ed or the like, they will not be read as active steps, but might be considered for the prior art. All verbs that are active steps to be accomplished in the method can end with “-ing”. This applies to “determined” or “used” in claims 72 and 82, “continued” and “determined” in claim 73, “determined” in claims 79, 80, and 83. However, for the purpose of compact prosecution, the examiner will consider the limitations as determining would be related to ways of examining effects, continuing would allow one to keep the treatment going and using would allow one to use particular techniques (e.g. of detection).
Tas teaches using cyclopamine to achieve therapeutic effect in human by causing differentiation of tumor cells and at the same time their apoptotic death (abstract and claims of Tas and paragraph 32). Tas teaches causation of apoptosis by a non-genotoxic mechanism (abstract). Tas teaches preserving the normal cells (abstract). Tas teaches intratumoral injections (paragraph 8). Tas teaches systemic administration (paragraph 34). Tas teaches Hh/Smo pathways (paragraph 9). Tas teaches disappearance of tumors (paragraphs 35-37). Tas teaches visual disappearance (paragraph 35 and claim 58 of Tas). Tas teaches six days after treatment (paragraphs 11 and 30). Tas teaches topical, non-topical or systemic administration and teaches forms of aqueous solution, liposomes, intratumoral injection, form for controlled release, dermal patch and cream, ointment or gel (paragraphs 51-57). Tas teaches immunohistochemical analysis of BCC’s (paragraph 13). Tas teaches disappeared tumor regions (paragraph 11). Tas teaches disappearance of several tumor areas within less than a week of cyclopamine exposure (paragraph 35). Claims 60-62 of Tas provide treating a human having a tumor. Tas teaches “The tumors are seen to have disappeared to leave behind large cystic structures containing little material inside and no detectable tumor cells.” (paragraph 37). Tas discussed optimal dosing and dosing and application schedules (paragraph 34). Tas teaches “Causation of highly efficient differentiation and apoptosis of the tumor cells in vivo by cyclopamine at doses that preserve the undifferentiated tissue cells are hitherto unknown achievements that, together with the non-genotoxic mode of action of cyclopamine, support the use of cyclopamine not only on BCC’s but also on those internal tumors that utilize the hedgehog/smoothened pathway for proliferation and for prevention of apoptosis and/or differentiation.” Tas teaches “Preservation of the undifferentiated cells in the normal epidermis and in hair follicles following exposure to cyclopamine, as described in this invention, provide information about the tolerable doses in other possible modes of administration as well; e.g. direct intratumoral injection of an aqueous solution or systemic administration of the same or of cyclopamine entrapped in liposomes.” (paragraph 34). Tas also recognizes that the doses/dose schedules it provides did not reveal any adverse effects on normal tissue/cells (paragraph 54).
Response to Applicant’s Arguments over the Rejection under USC 102(a)(1) over Tas
Applicant’s first argument (1) is that one would not recognize a disappearance of a tumor occurring on a patient by teachings of Tas ‘725 (a previously published application by applicant). The claim contains a method to administer the composition that is of the applicant’s claims, and therefore, will have the effects as applicant has shown. First, the prior art is presumed to be enabled for its teachings and efficacy is not a requirement for prior art enablement (MPEP 2121 I-III). If Tas ‘725 provides for disappearance then they are able to achieve it by carrying out a method, which is a method of applicant’s claims, then it will have such effects. The effects of the previously accomplished treatment in the prior art did not have to be recognized at the time of its invention (MPEP 2112). However, in the response to applicant’s next argument, the examiner points out the teaching from Tas ‘725 that were also used in this rejection.
Applicant’s second argument (2) is that applicant had pointed out causation of therapeutic effect is not directly show in Tas ‘725, and thus, cannot be anticipated as inherent. Applicant argues that no administration in the teachings of ‘725 would cause disappearance of a tumor. However, Tas ‘725 teaches methods to administer the composition that are of applicant’s own claims and it recognizes using effective amounts of the cyclopamine. Therefore, whether it was recognized then or not, the effect was achieved. However, Tas ‘725 does note in its teachings cause tumor disappearance and disappearance by visual disappearance as well as highly efficient apoptosis being caused by the administration. Tas ‘725 uses the same drug (cyclopamine, a known selective Hh/Smo inhibitor) as used in applicant’s current application, same administration type and same type of reasoning to use the drug (to cause apoptosis of the tumor cells). It will result in such effects that applicant indicates in their claims. The examiner did not avoid these limitations. For example, from the same rejection under USC 102 above, “Tas teaches intratumoral injections (paragraph 8). Tas teaches systemic administration (paragraph 34). Tas teaches Hh/Smo pathways (paragraph 9). Tas teaches disappearance of tumors (paragraphs 35-37). Tas teaches visual disappearance (paragraph 35 and claim 58 of Tas)” and “Tas teaches “Causation of highly efficient differentiation and apoptosis of the tumor cells in vivo by cyclopamine at doses that preserve the undifferentiated tissue cells are hitherto unknown achievements that, together with the non-genotoxic mode of action of cyclopamine, support the use of cyclopamine not only on BCC’s but also on those internal tumors that utilize the hedgehog/smoothened pathway for proliferation and for prevention of apoptosis and/or differentiation.”” Tas ‘725 also taught “Tas ‘725 teaches “The tumors are seen to have disappeared to leave behind large cystic structures containing little material inside and no detectable tumor cells.” (paragraph 37)”, where cystic structures with little material inside would be devoid spaces. Thus, sufficient teachings are provided by Tas ‘725 to anticipate applicant’s claims even the ones that applicant seems to indicate that Tas ‘725 does not teach.
Applicant indicates they amended claim 72 to rule out topical administrations. This is not observed in the claims. The options given for the formulation for administration in claim 72 include systemic (although non-oral), injection to a tumor, or for instillation to a body cavity. The instillation to a body cavity is not necessarily non-topical as it could be topically instilled to the interior of a nasal cavity or the oral cavity. The claim also uses “comprising” as a transition phrase and is open to other steps such as additional administrations. In the case of Tas ‘725, it points out the acceptable ways of administration and one is noted in the claims and disclosure of ‘725 as intratumoral injection. Thus, this route of administration that is also in applicant’s claims is anticipated for use in ‘725.
Applicant also argues in (2) that hundreds of tumor bearing patients were treated in the prior art by administrations of pharmaceutical compositions comprising a selective Hh/Smo signaling inhibitor is further objective evidence that causation of a therapeutic effect as in claim 72 did not occur. These other studies are not the study of Tas ‘725 which is the reference used in the rejection. It cannot be said what the other hundreds of prior art studies with these types of inhibitors have found in terms of tumor disappearance and/or no recurrence or whether they may contain teachings for further anticipation or obviousness of the claims.
Applicant’s third argument indicates that there are not sufficient details about the other non-topical modes of administration in Tas ‘725 in order to anticipate obtaining therapeutic effects that applicant has in the claims. It remains that Tas ‘725 does have more than sufficient details of administration and intratumoral injection is a recognized form of administration. Tas ‘725 recognizes that its doses are effective to have effects as applicant is arguing (i.e. tumor disappearance, causing cysts with no material/cells (devoid spaces) and efficient apoptosis as its mechanism). There is no indication in Tas ‘725 that intratumoral injection would not lead to such effects since it is an anticipated mode of administration for providing the same drug. These are facts and not opinions of the examiner.
Applicant’s fourth argument (4) is that they feel that examiner said the claims do not define dose. This is not the case. Examiner was indicating that the claims do not define a particular dose amount or particular rate or particular frequency in numerical terms. This was to give the applicant an option to consider using more defined doses, rates and/or frequencies if they felt it would overcome the rejection of record. Rather applicant uses language of “sufficiently high amount and rate and frequency of administration to cause apoptosis of the tumor cells with efficiency characterized by causation of empty spaces devoid of tumor cells within the tumor and/or by causation of a decrease in size of the tumor to less than half of pre-treatment size by day 5 from the starting of administration.” Such effects of tumor shrinking/disappearance and the forming of cysts without cells and material (empty spaces devoid of tumor cells) provide that such amounts, rates and frequencies were of the teachings of Tas ‘725. Tas ‘725 also teaches the mechanism of highly efficient apoptosis (of tumor cells) when administered to the patient. Tas ‘725 does teach tumor disappearance in its teachings. In addition, Tas ‘725 does indicate doses and dose schedules. Therefore, the teachings of Tas ‘725 provide amounts/rates/frequencies that are effective in these ways. When one is administering a drug, it always has an amount, a rate and frequency. Even if that was once for one time that day. The fact that Tas ‘725 recognizes the effects of providing the drug means the sufficiently high dosing to achieve them was anticipated.
Applicant points out and discusses figures of Tas ‘725 to try and show data of those figures would not anticipate the claimed method. It remains that the teachings of Tas ‘725 provide the teachings to anticipate the method. Again, the prior art is presumed enabled for its teachings (MPEP 2121 I-III). Applicant’s teachings still anticipate the method with the administration (including intra-tumor injection as a main option) of dose(s) of cyclopamine (a selective Hh/Smo signaling inhibitor) to subjects with tumors and the effects.
Applicant’s fifth argument (5) is that testing must be done to verify the findings in light of genetic heterogeneity of tumors and Tas ‘725 does not provide sufficient testing. However, the prior art is presumed to be enabled for its teachings and Tas ‘725 teaches administering the compound by an indicated form of intratumoral injection with ‘725’s recognition of achieving effects that applicant has also put in the claims (thus, the ‘725 dosing is anticipated to be sufficiently high).
Applicant’s sixth (6) argument is that prior art must describe every claim limitation and must describe them in combination as recited in the claim. Note MPEP 2131.02 “ A reference disclosure can anticipate a claim when the reference describes the limitations but "'d[oes] not expressly spell out' the limitations as arranged or combined as in the claim, if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination.” Kennametal, Inc. v. Ingersoll Cutting Tool Co.”. In this case, a person of skill in the art would envisage using intratumoral injections by teachings of ‘725 as it is taught as a suitable form for administration to treat the tumor. ‘725 sees all of its administrations of a composition with cyclopamine as working for its purposes.
For these reasons, the rejection under USC 102 over Tas ‘725 is maintained.
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.
Claim(s) 89-90 are rejected under 35 U.S.C. 103 as being unpatentable over Skvara et al (Journal of Investigative Dermatology, 2011, volume 131, pages 1735-1744) as evidenced by NCI (National Cancer Institute, NCI Dictionary of Cancer Terms, “complete response, downloaded April 2025) and as evidenced by Chen et al (Genes and Development, 2002, volume 16, pages 2743-2748), as evidenced by Che et al (Oncology Letters, 2013, volume 5, pages 1417-1421), as evidenced by Murphy et al (The American Journal of Pathology, 2006, volume 169, 1875-1885) and as evidenced by Pan et al (ACS Med Chem Letters, 2010, volume 1, pages 130-134).
Skvara teaches using LDE225 (a non-cyclopamine Smoothened pathway inhibitor) cream to treat basal cell carcinoma. In the beginning of the discussion it is noted that LDE225 is a selective antagonist of SMO that inhibits HH-dependent signaling (Discussion). It is indicated that out of 13 patients, 3 showed a complete response to LDE225 treatment (abstract and discussion). Skvara provides for a pro-apoptotic effect of the cream (figure 5, methods section). Skvara teaches “Three-dimensional (3D) surface reconstruction of the same lesion (f) before and (g) after treatment, showing a 79% volume reduction compared with baseline. Mean percentage (%) change from baseline in (h) tumor volume (P=0.011) and (i) tumor surface area (P=0.001) for basal cell carcinomas (BCCs) treated with 0.75% LDE225 cream (black) and vehicle (light gray) was measured on days (d) 8, 15, 22, and 29” (Figure 4 and Figure 4 legend of Skvara). Skvara teaches “In this experiment, distinct tumor cell apoptosis, measured by TUNEL staining, peaked after 3 days” (Discussion). In areas where cells undergo apoptosis, it will leave a void, particularly since Skvara shows a decrease in proliferation as well (also see discussion). Skvara provides for regression of murine basaloid tumor nests (Results, first section and figure 1). NCI evidences that a complete response (as found in some of the patients in Skvara) is the disappearance of all signs of cancer in response to the treatment (NCI definition of complete response). Skvara teaches a 1% or 3% solution in propylene glycol of LDE225 for application (LDE225 inhibits HH gene expression and prevents hair growth in mice and also Skin penetration/permeation studies ex vivo). These solutions provide for compositions of non-cyclopamine selective Hh/Smo inhibitor in sufficient amounts in non-aqueous solution where such a solution may be made suitable for injection or for instilling into a body cavity (e.g. nasal cavity or intraperitoneal cavity). Skvara teaches tumor imaging of samples (figures 1 and 4). Skvara does not provide for that there were any effects on angiogenesis, in vivo assay of blood vessel maintenance or an in vitro assay of capillary formulation by normal endothelial cells. There was an anti-proliferative and pro-apoptotic effect on the tumor cells in Skvara. Skvara teaches “In contrast, topically applied LDE225 showed an excellent safety profile with no local or systemic side effects, while being able to induce regression in all BCCs except one” and Skvara teaches possible persistent treatment to prevent recurrence of BCC’s at treated sites (last paragraph of discussion). Che evidences that cyclopamine had robust G1 cell cycle arrest and elicited notable effects on the expression of cyclin D1 through modulation of the MAPK/ERK signaling pathway (These are kinases) (abstract of Che). Che evidences that cyclopamine also suppresses levels of NfkappaB, MMP2 and MMP9 protein (abstract of Che). Che evidences that cyclopamine also downregulated the production of estrogen receptor alpha protein (abstract of Che). Che’s discussion evidences that cyclopamine has potent antiproliferative properties due to suppressing MAPK/ERK signaling. Chen evidences that cyclopamine has both teratogenic and antitumor activities (abstract). Pan evidences the that LDE225 is a potent and selective smoothened antagonist (abstract of Pan). Pan evidences that the compounds was screened against a large panel of receptors, ion channels, transporters, kinases and proteases and no appreciable activities were observed (second column of page 133). Murphy et al (The American Journal of Pathology, 2006, volume 169, pages 1875-1885) evidences that inhibiting endothelial ERK activation blocks angiogenesis (title and abstract of Murphy). Taking this evidence together, cyclopamine is a drug that has many more activities including suppressing MAPK/ERK signaling than the more selective LDE225, and thus, LDE225 has lower potential for inhibiting blood vessel maintenance or angiogenesis than cyclopamine based on limited range of effects that LDE225 has in the body compared to cyclopamine.
One of ordinary skill in the art before the time of filing would have utilized the teachings of Skvara (evidentiary references to evidence actions of LDE225 compared with cyclopamine, signaling in angiogenesis, and what a complete response is) to use a non-cyclopamine selective inhibitor of Hh/Smo signaling in a formulation for application to treat tumors which will lead to apoptosis of tumor cells, forming of voids where tumor cells have undergone apoptosis and used tumor images to examine for disappearance of the tumors. Skvara notes that some individuals had a complete response to treatment where all signs of a tumor were gone, and thus, tumor disappearance would have occurred. One of ordinary skill in the art would have made adjustments to dosing in Skvara to get even more patients to have complete responses and to provide for no recurrence of tumors if possible as this is desirable. One of ordinary skill in the art would observe the subjects to ensure treatment is successful. One of ordinary skill in the art before the time of filing would have made formulations of claims 89-90 as Skvara teaches non-aqueous solution formulations in Skvara as well as cream formulations with effective amounts of the active compound. Again, Skvara recognizes apoptosis of tumor cells in the tumor and complete responses to treatment. There is a reasonable expectation of success in using teachings of Skvara to provide for a tumor treatment method and effective tumor treating composition of the claims. As Skvara recognizes skin penetration of drug, a cream of Skvara can allow for non-oral systemic delivery as well as controlled release of the drug housed within the cream.
Claims 82-88 in addition to Claim(s) 89-90 are rejected under 35 U.S.C. 103 as being unpatentable over Skvara et al (Journal of Investigative Dermatology, 2011, volume 131, pages 1735-1744) and Au et al (2001, Journal of Controlled Release, Volume 74, pages 31-46) as evidenced by NCI (National Cancer Institute, NCI Dictionary of Cancer Terms, “complete response, downloaded April 2025) and as evidenced by Chen et al (Genes and Development, 2002, volume 16, pages 2743-2748), as evidenced by Che et al (Oncology Letters, 2013, volume 5, pages 1417-1421), as evidenced by Murphy et al (The American Journal of Pathology, 2006, volume 169, 1875-1885) and as evidenced by Pan et al (ACS Med Chem Letters, 2010, volume 1, pages 130-134).
Skvara teaches using LDE225 (a non-cyclopamine Smoothened pathway inhibitor) cream to treat basal cell carcinoma. In the beginning of the discussion it is noted that LDE225 is a selective antagonist of SMO that inhibits HH-dependent signaling (Discussion). It is indicated that out of 13 patients, 3 showed a complete response to LDE225 treatment (abstract and discussion). Skvara provides for a pro-apoptotic effect of the cream (figure 5, methods section). Skvara teaches “Three-dimensional (3D) surface reconstruction of the same lesion (f) before and (g) after treatment, showing a 79% volume reduction compared with baseline. Mean percentage (%) change from baseline in (h) tumor volume (P=0.011) and (i) tumor surface area (P=0.001) for basal cell carcinomas (BCCs) treated with 0.75% LDE225 cream (black) and vehicle (light gray) was measured on days (d) 8, 15, 22, and 29” (Figure 4 and Figure 4 legend of Skvara). Skvara teaches “In this experiment, distinct tumor cell apoptosis, measured by TUNEL staining, peaked after 3 days” (Discussion). In areas where cells undergo apoptosis, it will leave a void, particularly since Skvara shows a decrease in proliferation as well (also see discussion). Skvara provides for regression of murine basaloid tumor nests (Results, first section and figure 1). NCI evidences that a complete response (as found in some of the patients in Skvara) is the disappearance of all signs of cancer in response to the treatment (NCI definition of complete response). Skvara teaches a 1% or 3% solution in propylene glycol of LDE225 for application (LDE225 inhibits HH gene expression and prevents hair growth in mice and also Skin penetration/permeation studies ex vivo). These solutions provide for compositions of non-cyclopamine selective Hh/Smo inhibitor in sufficient amounts in non-aqueous solution where such a solution may be made suitable for injection or for instilling into a body cavity (e.g. nasal cavity or intraperitoneal cavity). Skvara teaches tumor imaging of samples (figures 1 and 4). Skvara does not provide for that there were any effects on angiogenesis, in vivo assay of blood vessel maintenance or an in vitro assay of capillary formulation by normal endothelial cells. There was an anti-proliferative and pro-apoptotic effect on the tumor cells in Skvara. Skvara teaches “In contrast, topically applied LDE225 showed an excellent safety profile with no local or systemic side effects, while being able to induce regression in all BCCs except one” and Skvara teaches possible persistent treatment to prevent recurrence of BCC’s at treated sites (last paragraph of discussion). Che evidences that cyclopamine had robust G1 cell cycle arrest and elicited notable effects on the expression of cyclin D1 through modulation of the MAPK/ERK signaling pathway (These are kinases) (abstract of Che). Che evidences that cyclopamine also suppresses levels of NfkappaB, MMP2 and MMP9 protein (abstract of Che). Che evidences that cyclopamine also downregulated the production of estrogen receptor alpha protein (abstract of Che). Che’s discussion evidences that cyclopamine has potent antiproliferative properties due to suppressing MAPK/ERK signaling. Chen evidences that cyclopamine has both teratogenic and antitumor activities (abstract). Pan evidences the that LDE225 is a potent and selective smoothened antagonist (abstract of Pan). Pan evidences that the compounds was screened against a large panel of receptors, ion channels, transporters, kinases and proteases and no appreciable activities were observed (second column of page 133). Murphy et al (The American Journal of Pathology, 2006, volume 169, pages 1875-1885) evidences that inhibiting endothelial ERK activation blocks angiogenesis (title and abstract of Murphy). Taking this evidence together, cyclopamine is a drug that has many more activities including suppressing MAPK/ERK signaling than the more selective LDE225, and thus, LDE225 has lower potential for inhibiting blood vessel maintenance or angiogenesis than cyclopamine based on limited range of effects that LDE225 has in the body compared to cyclopamine.
Skvara teaches the claims as discussed above.
Skvara does not teach intratumoral or systemic injections or instillation to a body cavity.
Au teaches determinants of drug delivery and transport (abstract). Au teaches that both systemic and regional chemotherapy are used in management of cancer patients with providing for intravenous system injection, intratumoral injection and direct instillation to a peritumoral space (small cavity in the body) (Introduction). Au provides its teachings apply to enhancing regional therapy as well as systemic therapy (Last paragraph of reference).
One of ordinary skill in the art before the time of filing would have utilized the teachings of Skvara (evidentiary references to evidence actions of LDE225 compared with cyclopamine, signaling in angiogenesis, and what a complete response is) to use a non-cyclopamine selective inhibitor of Hh/Smo signaling in a formulation for application to treat tumors which will lead to apoptosis of tumor cells, forming of voids where tumor cells have undergone apoptosis and used tumor images to examine for disappearance of the tumors. Skvara notes that some individuals had a complete response to treatment where all signs of a tumor were gone, and thus, tumor disappearance would have occurred. One of ordinary skill in the art would have made adjustments to dosing in Skvara to get even more patients to have complete responses and to provide for no recurrence of tumors if possible as this is desirable. One of ordinary skill in the art would observe the subjects to ensure treatment is successful. One of ordinary skill in the art before the time of filing would have made formulations of claims 89-90 as Skvara teaches non-aqueous solution formulations in Skvara as well as cream formulations with effective amounts of the active compound. Again, Skvara recognizes apoptosis of tumor cells in the tumor and complete responses to treatment. There is a reasonable expectation of success in using teachings of Skvara to provide for a tumor treatment method and effective tumor treating composition of the claims. As Skvara recognizes skin penetration of drug, a cream of Skvara can allow for non-oral systemic delivery as well as controlled release of the drug housed within the cream.
One of ordinary skill in the art before the time of filing would have looked to other methods of the prior art such as intratumoral injections and systemic administration in Au as these are common ways of delivering a cancer drug to the tumor site for its effects. It would be obvious to one of ordinary skill in the art to use systemic injections in situations where the tumor site would not be easily accessible for topical delivery. There is a reasonable expectation of success in utilizing these routine cancer drug administration techniques and getting successful delivery of the drug to the tumor site(s) particularly when the site would be hard to reach topically.
Response to Applicant’s Arguments over the Rejections under USC 103 over Skvara and over Skvara and Au
The examiner is withdrawing the rejection over Skvara alone for all claims except for claims 89-90 (composition claims), but maintaining the rejection over Skvara and Au. Skvara is mainly to topical administration, however, Au provides additional teachings that “both systemic and regional chemotherapy are used in management of cancer patients with providing for intravenous system injection, intratumoral injection and direct instillation to a peritumoral space (small cavity in the body) (Introduction). Au provides its teachings apply to enhancing regional therapy as well as systemic therapy (Last paragraph of reference)”.
Applicant argues that Skvara and Skvara and Au do not teach applicant’s claims and brings up multiple points.
Argument (1) of applicant provides that the topical application of LDE225 (a non-cyclopamine inhibitor of Hh/Smo signaling) at 0.75% in Skvara would not provide for therapeutic effects found by applicant. It is noted that Au motivates using intra-tumoral injections, intravenous injections and/or direct instillation to a peritumoral space as they enhance regional therapy as well as systemic therapy. The prior art combination of Skvara and Au teaches the administration of a non-cyclopamine selective Hh/Smo signaling inhibitor and provides for administration by forms of applicant’s claims with the advantage of therapy enhancement. Evidentiary references were used to show the inhibitory and cellular effects that are attributed to LDE225, which is the compound taught by Skvara as well as NCI for the meaning of complete response, which is presented in Skvara. There is a reasonable expectation from Au that by using administrations such as intra-tumor injections, intravenous injections and direct installation, one would enhance the effects of the drug therapy presented in Skvara. In the combination of Skvara and Au, one would produce the method of applicant’s claims and it would reasonably provide for the therapeutic effects as many of these are observed for use of LDE225 (characteristic effects of LDE225). The teachings of Skvara reasonably teach a composition as in claims 89-90 as it also recognizes a form of a 1% or 3% solution in propylene glycol of LDE225 for application (LDE225 inhibits HH gene expression and prevents hair growth in mice and also Skin penetration/permeation studies ex vivo). This composition has a dose of LDE225 (an non-cyclopamine inhibitor or Hh/Smo inhibitor) in form that would be acceptable for skin penetration (systemic delivery that is not oral) or that could be instilled into body cavities as a liquid solution. Note that limitations to intended use of a composition (claims 89-90) such as administration types do not carry patentable weight in a composition/product claim as along as the formulation of the prior art is in a form capable of such administrations and would be seen as having an effective dose. As Skvara motivates the use of LDE225 and its use for treatment of cancer, there is reasoning to optimize dosing to improve treatment and get more patients to complete responses.
Applicant argues by way of a clinical study related to Skvara’s work that Skvara was not enabled to provide the effects in the claim with its topical administration as it was skin irritating and ineffective when changed to a lower concentration. However, Skvara notes obtaining complete response in some subjects with its formulations. Therefore, it is seen as effective at the time of Skvara. Au motivates administration forms of applicant’s claims will enhance therapeutic effects while that change would provide administration that is not directly applied on skin. Thus, the combination of Skvara and Au provides for the teachings of applicant’s claims with a reasonable expectation of success and will be capable to of the effects on tumors as in applicant’s claims as administrations in Au would enhance the effects of the therapy in Skvara.
In argument (3) and argument (8), applicant argues providing arguments in the reply filed on June 13, 2025. However, Skvara was used in a 102 anticipation rejection and a different rejection under USC 103 over Skvara and Tas in a first non-final rejection after a request for continued examination. At that time, the examiner provided a second non-final rejection to address some further key points such as reconsideration of 112 rejections and reconsideration of Skvara, since there was no amendment to the claim. The rejections under USC 103 over Skvara and under USC 103 over Skvara and Au were not the same rejections that applicant had replied to from the non-final rejection filed on 4/11/2025.
In argument (4), applicant argues that claims 82 and 89 are not taught by the combination of the references with evidentiary references and indicates that the references of Murphy and Che teach away from applicant’s invention, however, Murphy and Che are only used as evidentiary references to make evident applicable signaling and cellular effects that occur with LDE 225/selective Hh/Smo inhibitor treatment of cells in Skvara. Evidentiary references are only used as evidence of what is occurring in the prior art. The Skvara and Au references are the basis of the rejection.
Applicant also argues in (4) that references provide for amino acid segments of Smo that are involved in non-transcriptional effects. Neither the reference used for the scope of enablement or Sasaki appear relevant to this 103 rejection over Skvara and Au.
In argument (5), applicant argues that Smo has transcriptional as well as non-transcriptional effects (claim says specifically no or less inhibition of non-transcriptional effect that supports blood vessel maintenance and/or angiogenesis where this is compared to cyclopamine), and thus, indicates the method is nonobvious. Applicant does not provide how LDE225 (a selective Hh/Smo signaling inhibitor with excellent safety profile), specifically, does not meet these limitations. LDE225 is the molecule from the teachings of Skvara.
In argument (6), applicant appears to argue the enablement of a non-cyclopamine molecule that has the effects as in claims 82 and 89. Then indicates the prior art has been teaching away from a non-cyclopamine molecule. LDE225 is not a cyclopamine molecule, and thus, the prior art of Skvara and Au is not teaching away from using non-cyclopamine molecules. In fact, LDE 225 seems to have a favorable safety profile in Skvara. Applicant again argues that the prior art should teach all features of the claim, Skvara teaches LDE225 (a non-cyclopamine selective Hh/Smo inhibitor) provided in doses to cause apoptosis of cancer cells with Au providing the motivation to use in the administration types of applicant’s claims to provide enhanced activity. The evidentiary references were provided to show that cyclopamine inhibits ERK kinase which would block cell proliferation and angiogenesis while LDE225 appears not to have a significant effect on kinases and seems to have a good safety profile. Cyclopamine is recognized as being teratogenic. Thus, there is a reasonable indication by evidence that LDE225 has more specificity and better safety than cyclopamine and will have less effects on pathways that would affect blood vessel maintenance and/or angiogenesis, which are key to an organism. Therefore, the teachings of Skvara and the teachings of Skvara in combination with Au teach the claims with a reasonable expectation of success in achieving compositions and methods of applicant’s claims. The effects of the treatment are controlled mainly by the pharmaceutical agent and as Skvara teaches such a pharmaceutical agent, it is capable of providing all the effects after its administration by means known in the prior art. As Skvara also recognizes effectiveness in cancer and better safety profile, one would also be capable of optimizing the amounts as necessary to achieve the desired, optimal effects in treating the tumor.
Argument (7) indicates there were not a finite number of predictable solutions, and thus, it was not expect such a non-cyclopamine molecule of the claims would provide beneficial results. Applicant does not have any examples testing a non-cyclopamine molecule as claimed being used in the manner claimed. Therefore, it remains that the prior art, which teaches a specific non-cyclopamine compound that is also an inhibitor of Hh/Smo signaling and compositions thereof that are administered to treat tumors/cancer cells would provide these effects when administered. Prior art also recognizes the advantage of using administration forms like intratumoral injection. MPEP 2112 sections I-III where something old does not become patentable upon the discovery of a new property, inherent features need not be recognized at time of the prior art invention and a rejection under USC 102 or 103 can be made when the prior art product seems to be identical other than a silent inherent characteristic (in this case the effects after administration of the composition with the compound). In regards to part IV of MPEP 2112, the examiner has provided evidentiary references of Che, Chen, Murphy and Pan as well as the combined teachings of Skvara and Au to provide for presence of the effects. The NCI evidentiary reference is just to define the meaning of complete response in the art of cancer treatment.
Inherency can be demonstrated from a combination of elements and may come from a combination of references (MPEP 2112 IV – ““[I]n order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis – the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art.” Id. at 1195-96, 112 USPQ2d at 1952. But see, Persion Pharms. LLC v. Alvogen Malta Operations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is “the natural result of the combination of prior art elements.” (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020).” In this case when Skvara is used by administration methods of Au, applicant will be able to achieve increased efficacy, more apoptosis of tumor cells and more disappearance of tumors (a complete response), since Skvara already recognizes complete responses when used topically. Enhancements by using administrations of doses by Au will enhance this effectiveness.
For these reasons, the rejections under USC 103 over Skvara and over Skvara and Au are maintained as they still teach the claimed composition and method.
Claim 73 and 80 in addition to 72, 77-79 and 81 is rejected under 35 U.S.C. 103 as being unpatentable over Tas US 20100048725.
Tas ‘725 teaches the claims as discussed above. Tas teaches visual disappearance (paragraph 35) and immunohistochemical criteria (paragraph 42). Tas teaches topical, non-topical or systemic administration and teaches forms of aqueous solution, liposomes, intratumoral injection, form for controlled release, dermal patch and cream, ointment or gel (paragraphs 51-57) and intra-tumoral injection. Claim 68 of Tas ‘725 provides for intratumoral or topical or systemic administration. Thus, one of ordinary skill in the art could choose to do a combination of topical and intratumoral injections by the teachings of 725. Paragraph 7 also provides topical with paragraph 8 providing in a further aspect administering by non-topical means including intratumoral injections.
Tas ‘725 does not teach undetectability by day 5 and then continued administration for up to 2 more days after causation of undetectability of the tumor is determined not to cause intolerable effects in the subject and determining the administration caused disappearance of the tumor without recurrence.
One of ordinary skill in the art before the time of filing would have made adjustments to the method to include further treatment after tumor disappearance is observed as Tas provides for optimizing dosing and application schedules. One of ordinary skill in the art would also seek to continue treatments for cancer to achieve full treatment so that a tumor does not reoccur. Through adjustment of application schedules, one would add time to further ensure the effect of the treatment in ridding the body of cancerous tumors and cancer cells. One of ordinary skill in the art would continue dosing until desired outcomes in cancer treatment are provided to the patient. One of ordinary skill in the art would follow up and monitor patients to check on the status of treatment where Tas recognizes such visualization/observing. Thus, there would be a reasonable expectation of applying teachings of Tas ‘725 to further continue treatment after an observed disappearance of the tumor(s) in the patient. The amount of time would be dependent on the needs of the patient. In regards to amended claim 80 where applicant adds topical administration in addition to the injection to a tumor. Tas ‘725 provides for both option of topical and intratumoral injections, thus, allowing for administering by both topical and intratumoral injection means.
Response to Applicant’s Arguments over the Rejection under USC 103 over Tas (‘725)
Claim 80 (a dependent claim) was amended to indicate the subject is administered with a composition for injection to tumor and also with a composition for topical administration. The undetectability has now been adjusted to by day 5 and the continuation of administration is adjusted to up to 2 more days after causation of undetectability. These amendments need consideration of the prior art and both topical and intratumoral administrations are found in teachings of Tas.
Claim 73 was previously taught in this rejection under USC 103, however, applicant’s amendments to claim 80 required updated explanation of the combination of administrations (topical and intra-tumoral), which are both administrations already provided by Tas’s teachings.
In argument (1), applicant argues that there was no patient treated in ‘725, and thus, therapeutic efficacy could not occur. Again, the prior art is considered enabled for its teachings (MPEP 2121). However, ‘725 provides for administering to subjects with tumors by topical, non-topical, and thus, anticipates carrying out this method. By doing so, such effects would be reasonably achieved. ‘725 provides the cyclopamine, compositions and administration limitations of the claims as well as recognition of being effective for tumor cell apoptosis, forming cysts with no material inside (devoid of cells), shrinking/reducing tumors, and tumor disappearance. As ‘725 allows both the topical and intratumoral injection administration in its teachings, one of ordinary skill in the art would be able to subject the subjects with tumors to both administrations. Dosing would be adjusted for desired results (paragraph 34 of Tas ‘725) such as to more quickly cause tumor disappearance. As was stated previously, one of ordinary skill in the art would also continue treatments for the desired results of ensuring tumor disappearance. As teachings are found in ‘725 to allow for applicant’s method, it was capable of these effects when administered to a subject.
In argument (2), applicant argues that they feel it is not pointed out that optimizations were done. ‘725 teaches that optimizations would be performed for dosing (paragraph 34 of ‘725). This would lead one of ordinary skill in the art to routinely optimize (see MPEP 2144.05). Applicant argues that topical administration provides adverse effects, however, ‘725 also recognizes other forms of administration including intratumoral administration. Paragraph 32 of ‘725 provides for “Lack of adverse effects of the described treatment is confirmed also by the presence of clinically normal-looking healthy skin and hair at the sites of cyclopamine application in patients (longest duration of follow-up of a human subject is over 31 months at the time of writing and shows safety of the treatment also in the long term)”. ‘725 was also pointed out to cause little or no genotoxicity. It appears, again, that ‘725 has the teachings to carry out applicant’s methods in these claims.
In argument (3), applicant argues there would not be a reasonable expectation of success for reasons involving numerous cell types, targets, possible non-transcriptional effects, and non-conventional investigations. It remains that Tas ‘725 provides the teachings to carry out applicant’s method with a specific drug, cyclopamine. In doing so, the observed effects would be reasonably achieved in claims 73 and 80 in this rejection under USC 103.
In argument (4), applicant argues there are indica of non-obvious including the therapeutic results on the one patient, results applicant feels are unexpected, a long-felt need for the treatment and prior art being shown to fail at results such as tumor disappearance without recurrence. As explained above, the results are expected and achievable by the teachings of Tas ‘725. The need is considered met by the teachings of Tas ‘725 and other prior art cited herein. The prior art is presumed to solve the problem by the methods of Tas ‘725 where Tas ‘725 also allows optimization of dosing and notes similar effects that applicant is claiming and arguing.
In argument (5), applicant argues that with unknown items from applicant’ specification, one would not be able to carry out the method as claimed and that the prior art saw the problem as not being solved. However, Tas ‘725 provides the teachings of the administration of cyclopamine (a selective Hh/Smo inhibitor) in manners as claimed with teachings of effects applicant is claiming to occur after such treatments (e.g. apoptosis of tumor cells, tumor disappearance, etc.). Tas ‘725 also provides for optimization of dosing where one of ordinary skill in the art would optimize to achieve effects ‘725 notes such as apoptosis of tumor cells and tumor disappearance. This would be optimized to make sure the tumors stay gone (no recurrence).
For these reasons, the rejection under USC 103 over ‘725 is also maintained.
Non-Statutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 72, 73, 77-81 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-9, 11-13, 15-21, and 23 of U.S. Patent No. 7893078.
Where verbs are presented in past tense with -ed or the like, they will not be read as active steps, but might be considered for . All verbs that are active steps to be accomplished in the method can end with “-ing”. This applies to “determined” or “used” in claims 72 and 82, “continued” and “determined” in claims 73 and 84, “determined” in claims 79, 80, and 83. However, for the purpose of compact prosecution, the examiner will consider the limitations as determining would be related to ways of examining effects, continuing would allow one to keep the treatment going and using would allow one to use particular techniques (e.g. of detection).
The claims of Tas (‘078) teach using cyclopamine to achieve therapeutic effect by causing differentiation of tumor cells and at the same time their apoptotic death (abstract and claims of Tas). Tas teaches causation of apoptosis by a non-genotoxic mechanism (abstract). Tas teaches preserving the normal cells (abstract). Tas teaches intratumoral injections (paragraph 8). Tas teaches systemic administration (paragraph 34). Tas teaches Hh/Smo pathways (paragraph 9). Tas teaches disappearance of tumors (paragraphs 35-37). Tas teaches visual disappearance (paragraph 35). Tas teaches six days after treatment (paragraphs 11 and 30).
Response to Applicant’s Arguments over Obviousness-Type Double Patenting Rejections
Applicant argues that the double patenting rejection over ‘078 should be overcome for similar reasons as for the rejection over US 2010/0048725 (the Tas reference used as a 102 rejection). For the reasons, the rejection under USC 102 is being maintained over Tas, the claims of ‘078 remain rejected under non-statutory double patenting.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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/MARK V STEVENS/Primary Examiner, Art Unit 1613