Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Response to Amendment
Acknowledgment is made of the receipt and entry of the amendment filed on 04/28/2026, wherein claims 7-8 and 10-11 were cancelled, new claim 21-28 are added, claims 1 and 5 are amended to recite the α1-blocker is tamsulosin and synergistic inhibition limitation “thereby providing a synergistic inhibition of the contraction that is at least 13% greater than the inhibition from the corresponding treatment with onvansertib or the α1- blocker alone”. Applicant elected Group II of inhibiting non-adrenergic smooth muscle contraction, and tamsulosin as the single α1-blocker species without traverse in the reply filed 07/31/2024. As noted in office action mailed 02/21/2025 , independent claim 1 of Group I is considered to extent of treating BPH associated with smooth muscle contraction with onvansertib in combination with tamsulosin.
Status of Claims
Claims 1, 3, 5 and 13-28 are pending and under examination in this office action.
Priority
This application 17/433,440, filed on 08/24/2021, is a 371 of PCT/US2020/019647 filed 02/25/2020 which claims benefit of US provisional applications 62/810,171 filed on 02/25/2019.
It’s noted NO experiment wherein contraction of human prostate smooth muscle indued by other agent (e.g. endothelin-1) or ATP (purinergic) was disclosed in US provisional applications 62/810,171.
Claim Interpretation
Claim 1 is amended to recite a method of treating benign prostatic hyperplasia (BPH) in a patient, comprising treating the patient with (a) onvansertib and (b) tamsulosin, wherein the BPH is associated with non-adrenergic contraction of a prostate smooth muscle induced by an electric field stimulation (EFS) at about 32 Hertz (Hz) or a corresponding neurogenic action potential, thereby providing a synergistic inhibition of the contraction that is at least 13% greater than the inhibition from the corresponding treatment with onvansertib or the α1- blocker alone.
Claim 5 is amended to recite a method of inhibiting non-adrenergic contraction of a prostate smooth muscle induced by an electric field stimulation (EFS) at about 32 Hertz (Hz) or a corresponding neurogenic action potential in a patient having benign prostatic hyperplasia (BPH), comprising treating the prostate smooth muscle of the patient in need thereof with (a) an effective amount of onvansertib and (b) an effective amount of an α1- blocker , wherein the α1- blocker is tamsulosin, thereby providing a synergistic inhibition of the contraction that is at least 13% greater than the inhibition from the corresponding treatment with onvansertib or the α1- blocker alone.
Please note the limitation “thereby... 13% greater than...” is considered as intended result/treatment outcome of administering combination of onvansertib and tamsulosin, which does not materially limit the claimed method since such limitations do not result in manipulative difference in method steps of administering the active drugs. Please also note pharmacological/biological activities are properties of active agents. Inhibiting contraction of a smooth muscle (adrenergic, non-adrenergic) or induced by action potential or other mechanism is considered as properties of onvansertib and/or tamsulosin and direct result of administering onvansertib and/or tamsulosin to the subject in need thereof. MPEP 2112.I. states: "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Action Summary/Response to Arguments
Applicant’s remarks filed 04/28/2026 have been fully considered, but they are NOT persuasive to overcome scope of enablement rejection under 35 USC 112(a) and 35 USC 103 rejections on the record. The scope of enablement rejection is reapplied/reiterated as necessitated by amendment. Please see the response to argument in following sections.
As necessitated by amendment, claims 1, 3, 5 and 13-28 are newly rejected for failing to comply with written description requirement under 35 USC 112(a).
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o).
Instant claims are amended to recite limitation “thereby providing a synergistic inhibition of the contraction at least 13% greater than the inhibition from the corresponding treatment with onvansertib or the α1- blocker alone”. However, instant specification does not disclose any inhibition of contraction at least 13% greater than the inhibition from the corresponding treatment with onvansertib or the α1- blocker alone.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Written Description Rejection (New rejection necessitated by amendment)
Claims 1, 3, 5 and 13-28 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 instantly claimed method of inhibiting non-adrenergic contraction of a prostate smooth muscle induced by neurogenic action potential in a patient having benign prostatic hyperplasia (BPH), or treating BPH associated with non-adrenergic contraction of a prostate smooth muscle induced by neurogenic action potential, with any combination of onvansertib and tamsulosin that provides synergistic inhibition of the contraction at least 13% greater than the inhibition from the corresponding treatment with onvansertib or the α1- blocker alone. This is a written description rejection, rather than an enablement rejection under 35 U.S.C. 112, first paragraph. Applicant is directed to the MPEP 2163 and Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1st "Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.
MPEP 2163.02 states “ Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, the inventor was in possession of the invention, and that the invention, in that context, is whatever is now claimed”. The Applicant is required to provide adequate written description to support the newly added limitation “ non-adrenergic contraction of a prostate smooth muscle induced by neurogenic action potential” and “a synergistic inhibition of the contraction that is at least 13% greater than the inhibition from the corresponding treatment with onvansertib or the α1- blocker alone”.
Instant specification disclosed in-vitro assay of onvansertib alone on adrenergic contraction (Figures 1), and non-adrenergic contraction induced by EFS, endothelin-1 and ATP (See Figures 2-3). Instant specification disclosed assay of α1-blocker (e.g. tamsulosin 300nM) alone on EFS or noradrenaline-induced contraction(See Figure 4). Instant specification disclosed assay of onvansertib (100nM) in combination with α1-blocker (e.g. tamsulosin 300nM) on EFS - induced contraction(See Figure 5). Instant specification does not disclose any other combination of onvansertib with tamsulosin at different concentration/amount. Instant specification does NOT disclose any assay of onvansertib in combination with tamsulosin on endothelin-1 induced or ATP induced contraction, or other non-adrenergic contraction induced by neurogenic action potential. Instant specification does not disclose the assay activity/results are associated with neurogenic action potential. All experiment of instant specification are directed to in-vitro assay with human prostate tissues. NO experiment in instant specification are directed to in-vivo assay of smooth muscle contraction in a patient exhibiting prostatic hyperplasia (BPH) or any other pathological conditions.
It’s noted EFS simulates action potentials result in the release of endogenous neurotransmitters, including noradrenaline (Spec, page 11, lines 10-13). However, noradrenaline-induced contraction is adrenergic, NOT instantly claimed non-adrenergic contraction. Smooth muscle contraction can be induced by both adrenergic and non-adrenergic mechanisms, and action potentials play crucial role in both mechanism. As instant specification disclosed (See page 22), “Whether onvansertib addresses the same or different intracellular signaling pathways to inhibit smooth muscle contraction and proliferation, and which other effectors take part together with PLK1 in onvansertib-sensitive signaling, cannot be estimated on the basis of our data”. Thus, the new limitation drawn to the non-adrenergic contraction of a prostate smooth muscle induced by neurogenic action potential is not fully supported by instant specification.
Further, instant specification does not disclose the “synergistic inhibition of the contraction that is at least 13% greater than the inhibition from the corresponding treatment with onvansertib or the α1- blocker alone”. It’s noted the alleged 13% greater synergistic inhibition is based on the calculated inhibition by Bliss model as shown in Applicant’s Remarks ( page 8-10): “In sum, the 79% inhibition observed from the claimed combination exceeds the Bliss predicted 66% inhibition, additive of onvansertib and tamsulosin acting independently, by at least 13 percentage points”. However, instant specification does not disclose the observed total inhibition of onvansertib/tamsulosin is 79% or 66% calculated inhibition based on Bliss model. An ordinary skilled in the art would not know how the “13 percentage points” is calculated at the time when instant application was filed. The specification does not provide sufficient support for instant claimed method of inhibiting smooth muscle contraction induced by neurogenic action potential in a patient having benign prostatic hyperplasia (BPH) with any combination of onvansertib and tamsulosin that could achieve instant alleged synergistic inhibition. For example, an ordinary skilled in the art would not know if 50 nM of onvansertib in combination of 50 nM of tamsulosin could achieve the alleged 13% greater synergistic inhibition.
Regarding the method of treating benign prostatic hyperplasia (BPH) associated with contraction of smooth muscle with onvansertib, instant specification only speculates onvansertib is possible candidate to be tested in vivo in the context of LUTS suggestive of BPH treatment (See page 23):”It appears possible that onvansertib may reduce prostate smooth muscle tone and growth at once in BPH, so that onvansertib could be an attractive compound to be tested in vivo in the context of LUTS suggestive of BPH”. An ordinary skilled in the art would not be appraised the efficacy of onvansertib for treating BPH associated with smooth muscle contraction in absence of in-vivo assay due to high unpredictability of smooth muscle contraction, let alone the combination of onvansertib and tamsulosin. It’s noted instant specification does not disclose any assay of onvansertib and tamsulosin wherein symptoms of BPH are reduced or urinary flow is improved as recited in instant claim 3.
As elaborated, the specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed . Applicant is reminded that MPEP 2161 II makes clear that “The written description requirement is separate and distinct from the enablement requirement”.
Scope of enablement rejection(newly reapplied as necessitated by amendment).
Claims 1, 3, 5 and 13-28 are rejected under 35 U.S.C. 112(a) first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one 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. The specification, while being enabling for a method of inhibiting EFS induced prostate smooth muscle contraction by administering specific combination of onvansertib with tamsulosin at certain concentration/amount, does not reasonably provide enablement for inhibiting non-adrenergic smooth muscle contraction induced by neurogenic action potential in a patient having BPH, or treating benign prostatic hyperplasia (BPH) associated with non-adrenergic smooth muscle contraction induced by neurogenic action potential with any combination of onvansertib with tamsulosin at any amount/ concentration that could achieve the alleged synergistic inhibition at least 13% greater than the inhibition from the corresponding treatment with onvansertib or the α1- blocker alone. This is a scope of enablement rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). The determination that "undue experimentation" would have been needed to practice the claimed invention in full scope is not a single, simple factual determination.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) 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.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The Breadth of The Claims/ Nature of The Invention
Instant claims are amended to recite a method of inhibiting non-adrenergic smooth muscle contraction induced by neurogenic action potential in a patient having BPH, or treating benign prostatic hyperplasia (BPH) associated with non-adrenergic smooth muscle contraction induced by neurogenic action potential, with combination of onvansertib with tamsulosin that provides synergistic inhibition at least 13% greater than the inhibition from the corresponding treatment with onvansertib or the α1- blocker alone.
Instant specification disclosed working examples comprising onvansertib (100nM) in combination with α1-blocker (e.g. tamsulosin 300nM) were tested on EFS-induced contractions of human prostate strips as disclosed in instant specification (Fig. 5). Instant specification disclosed “EFS simulates action potentials, resulting in the release of endogenous neurotransmitters, including noradrenaline (See page 11 ). Accordingly, instant claim 5 is enabled for a method of inhibiting contraction of prostate smooth muscle induced by EFS with specific combination of onvansertib with tamsulosin. However, instant claims are amended to recite synergistic inhibition of smooth muscle contraction induced by neurogenic action potential in a patient having BPH. Instant specification does not provide adequate support for the alleged synergistic inhibition. Specifically, instant claims encompass numerous combination of onvansertib with tamsulosin, while instant alleged synergistic inhibition would not be achieved by any combination of onvansertib with tamsulosin.
The State of the Prior Art and the Predictability or Lack Thereof in the Art
There are variety of factors/mechanism involved in smooth muscle contraction and inhibiting smooth muscle contraction is highly unpredictable. Regarding the smooth muscle contraction induced by EFS or “neurogenic action potential” , there are variety of agents that can induce action potentials in smooth muscle, e.g. hormones like tetrodotoxin/ oxytocin, neurotransmitters (e.g. norepinephrine and acetylcholine), and mechanical stimulation(e.g. EFS). These agents activate signaling pathways that cause an influx of calcium ions into the cell, which depolarizes the cell membrane and triggers an action potential. Instant specification only disclosed EFS simulates action potential resulting in the release of endogenous neurotransmitters, including noradrenaline (Spec, page 11, lines 10-13)., However, noradrenaline-induced contraction is adrenergic, NOT instantly claimed non-adrenergic contraction.
With respect to inhibiting contraction of smooth muscle of prostate tissues associated with benign prostatic hyperplasia (BPH), Hennenberg’ 2017 teaches “lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia may be caused by prostate smooth muscle contraction. Although α1 -blockers may improve symptoms by prostate smooth muscle relaxation, their efficacy is limited. This may be explained by non-adrenergic mediators causing contraction in parallel to α1-adrenoceptors. However, little is known about the relevance and cooperative actions of non-adrenergic mediators in the prostate”(See Background, Introduction). Hennenberg’ 2017 states: “Although some previous studies addressed prostate smooth muscle contractions by non-adrenergic mediators, a systematic study using comparable conditions is to the best of our knowledge lacking. A previous study was performed to compare several mediators, but this did not include endothelins and thromboxane, and no comparisons to KCl-induced contraction. Most importantly, that study used tissues of mixed origin, so that comparison was possible only between tissues from TURP and retropubic prostatectomy” (See page 704, right column). Hennenberg’ 2017 teaches α1 blocker (e.g. tamsulosin) respond differently to non-adrenergic smooth muscle contraction of prostate cell or tissues induced by different mediators (e.g. endothelins, U46619, dopamine, etc. ) (See Abstract/Results, Figure 1).
Hennenberg’ 2018 teaches effects of Polo-Like Kinase (PLK) inhibitors (e.g. SBE 13, cyclapolin 9, etc.) on non-adrenergic smooth muscle contraction of human prostate tissues, wherein contractions were induced by electric field stimulation (EFS), endothelin-1, etc. in organ bath(See Abstract, Methods). Hennenberg’ 2018 teaches EFS simulates action potentials, resulting in the release of endogenous neurotransmitters, including norepinephrine. Using the inhibitor for neurotransmitter release, tetrodotoxin, it has been previously demonstrated, that this accounts for two-thirds of EFS-induced contraction in the human prostate( See page 4, right column). Hennenberg’ 2018 teaches adrenergic and non-adrenergic prostate contraction share some common intracellular pathways, but different PLK inhibitor responds differently to non-adrenergic smooth muscle contraction induced by different mediators(See Abstract/Result, Figures 4-6). As such, inhibiting contraction of smooth muscle of prostate cell or tissues associated with benign prostatic hyperplasia (BPH) with α1 blocker and/or PLK inhibitor is highly unpredictable.
More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity (e.g., cancer prevention) is generally considered an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The Amount of Direction Present and Presence or Absence of Working Examples
The specification does not provide sufficient working examples for a skilled artisan to practice the claimed method of inhibiting smooth muscle contraction induced by neurogenic action potential in a patient having benign prostatic hyperplasia (BPH) with combination of onvansertib and tamsulosin in its full scope.
Instant specification disclosed in-vitro assay of onvansertib alone on EFS, endothelin-1 and ATP induced contraction (See Figures 1-3). Instant specification disclosed assay of α1-blocker (e.g. tamsulosin 300nM) alone on EFS, noradrenaline-induced contraction(See Figure 4). Instant specification disclosed assay of onvansertib (100nM) in combination with tamsulosin( 300nM) on EFS - induced contraction(See Figure 5). Instant specification does not disclose any other combination of onvansertib with tamsulosin at different concentration/amount that exhibit instant alleged synergistic inhibition. Instant specification does NOT disclose any assay of onvansertib in combination with tamsulosin on endothelin-1 induced or ATP induced (purinergic) contraction, or other non-adrenergic contraction, or other contraction induced by action potential. Instant specification does not disclose the assay activity/results are associated with neurogenic action potential. All experiment of instant specification are directed to in-vitro assay with human prostate tissues. NO experiment in instant specification are directed to in-vivo assay of smooth muscle contraction in a patient exhibiting prostatic hyperplasia (BPH). As instant specification disclosed (See page 22), “Whether onvansertib addresses the same or different intracellular signaling pathways to inhibit smooth muscle contraction and proliferation, and which other effectors take part together with PLK1 in onvansertib-sensitive signaling, cannot be estimated on the basis of our data”.
Regarding the method of treating benign prostatic hyperplasia (BPH) associated with contraction of smooth muscle with onvansertib, instant specification only speculates onvansertib is possible candidate to be tested in vivo in the context of LUTS suggestive of BPH treatment (See page 23):”It appears possible that onvansertib may reduce prostate smooth muscle tone and growth at once in BPH, so that onvansertib could be an attractive compound to be tested in vivo in the context of LUTS suggestive of BPH”. An ordinary skilled in the art would not be appraised the efficacy of onvansertib for treating BPH associated with smooth muscle contraction in absence of in-vivo assay, let alone the alleged synergistic inhibition by combination of onvansertib and tamsulosin. It’s noted instant specification does not disclose any assay of onvansertib and tamsulosin wherein symptoms of BPH are reduced or urinary flow is improved as recited in instant claim 3.
The level of one of ordinary skill in the art
The level of skill required to make and/or use the instant invention would likely require many years of professional experience conducting research in the art (e.g., medicine, pharmaceutical science, biology, biochemistry, medicinal chemistry, and/or organic chemistry, etc.) as well as an advanced educational degree (e.g., M.D. and/or Ph.D.) commensurate in level with the advanced techniques involved in the preparation and/or use of the instant invention.
The quantity of experimentation needed
It would be a great burden for one of ordinary skill in the art to carry out undue experimentation to use the claimed invention in full scope. The dosage of onvansertib and tamsulosin recited in instant claims 21-28 are based on in-vitro assay which might not translate into therapeutically effective dosage regimen in patients having BPH. Working examples would be needed to determine the therapeutically effective dose for the combination of onvansertib and tamsulosin, respectively, which may vary depending on many factors , such as the subjects being treated wherein the contractions induced by different neurogenic action potentials , the disease condition and intended treatment outcome, etc. In-vivo experiment in a patient exhibiting prostatic hyperplasia (BPH) would be needed to evaluate the efficacy( e.g. urinary flow, Qmax) of instantly claimed method treating BPH in a patient with different combination of onvansertib and tamsulosin .
Conclusion
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562,27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here with respect to the claimed method of inhibiting smooth muscle contraction or method of treating benign prostatic hyperplasia (BPH) associated with smooth muscle contraction induced by neurogenic action potential, comprising administering any combination of onvansertib with tamsulosin that could achieve the alleged synergistic inhibition. In other words, one skilled in the art could not practice the claimed invention without undue experimentation.
Response to Arguments
Applicant argues independent claim 5 has been amended to recite "[a] method of inhibiting non-adrenergic contraction of a prostate smooth muscle induced by an electric field stimulation (EFS) at about 32 Hertz (Hz) or a corresponding neurogenic action potential" ... one skilled in the art
would understand that electric field stimulation (EFS)-induced contraction is a well-accepted proxy for contraction induced by "a corresponding neurogenic action potential" under pathological
conditions... Application of EFS simulates action potentials, resulting in the release of endogenous
neurotransmitters, including noradrenaline...(Remarks, page 5-6).
RESPONSE: Applicant’s argument is fully considered, but NOT persuasive. The amended claim 5 is enabled for a method of inhibiting contraction of prostate smooth muscle in vitro induced by EFS with certain combination of onvansertib with tamsulosin at specific concentration/amount. It’s noted EFS simulates action potentials resulting in the release of endogenous neurotransmitters, including noradrenaline. However, noradrenaline-induced contraction is adrenergic, NOT instantly claimed non-adrenergic contraction.
Further, instant claims are amended to recite “synergistic inhibition”. Instant specification disclosed assay of onvansertib (100nM) in combination with tamsulosin( 300nM) on EFS - induced contraction(See Figure 5). Instant specification does not disclose any other combination of onvansertib with tamsulosin at different concentration/amount that exhibit instant alleged synergistic inhibition. Thus, instant claimed synergistic inhibition is not fully supported and enabled by instant specification.
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.
Claims 1, 3, 5, 13- 28 are 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 1 is amended to recite a method of treating benign prostatic hyperplasia (BPH) in a patient, comprising treating the patient with (a) onvansertib and (b) tamsulosin, wherein the BPH is associated with non-adrenergic contraction of a smooth muscle induced by EFS or corresponding neurogenic action potential. Claim 5 is amended to recite a method of inhibiting non-adrenergic contraction of a smooth muscle induced by EFS or corresponding neurogenic action potential comprising treating the smooth muscle with (a) onvansertib and (b) tamsulosin. Instant specification disclosed “Application of EFS simulates action potentials, resulting in the release of endogenous neurotransmitters, including noradrenaline” (See page 11, para2 ). However, noradrenaline-induced contraction is adrenergic, NOT instantly claimed non-adrenergic contraction. Smooth muscle contraction can be induced by both adrenergic and non-adrenergic mechanisms, and action potentials play crucial role in both mechanism. As such, the limitation regarding non-adrenergic contraction of a smooth muscle induced by EFS or neurogenic action potential is inconsistent/contradictory and indefinite. Dependent claims 3 and 13-28 are also rejected due to dependency on claims 1 and 5.
Response to Arguments
Applicant argues independent claims 1 and 5 have been amended to recite " non-adrenergic contraction of a prostate smooth muscle induced by an electric field stimulation (EFS) at about 32 Hertz (Hz) or a corresponding neurogenic action potential" ... one skilled in the art would understand that electric field stimulation (EFS)-induced contraction is a well-accepted proxy for contraction induced by "a corresponding neurogenic action potential" under pathological conditions...(Remarks, page 6).
RESPONSE: Applicant’s argument is fully considered, but NOT persuasive. It’s noted EFS simulates action potentials resulting in the release of endogenous neurotransmitters, including noradrenaline. However, noradrenaline-induced contraction is adrenergic, NOT instantly claimed non-adrenergic contraction. Thus, the limitation regarding non-adrenergic contraction of a smooth muscle induced by EFS or neurogenic action potential is inconsistent/contradictory.
Reiterated /Reapplied rejections necessitated by amendment
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 5, 13- 20 are rejected under 35 U.S.C. §103 as being unpatentable over Valsasina et al.( US 2012/0114641 A, Applicant’s IDS dated 06/16/2023), in view of Flomax® (tamsulosin hydrochloride) label (2009, retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020579s026lbl.pdf)
Claim interpretation: Instant specification ( page 2 and 3) discloses onvansertib (also known as PCM-075, NMS-1286937, NMS-P937, "compound of formula (I)" in U.S. Patent 8,927,530; IUPAC name 1-(2-hydroxyethyl)-8-{[5-(4-methylpiperazin-l-yl)-2- (trifluoromethoxy) phenyl] amino}- 4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline-3-carboxamide).
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Regarding active compound onvansertib, Valsasina discloses therapeutic combination comprising a compound of formula I (AKA, onvansertib, a PLK1 inhibitor) and a method of treating or delaying progression of cell proliferative disorders (e.g. benign prostatic hyperplasia BPH) with combination comprising onvansertib (See abstract, [0005]-[0010], [0048]).
Regarding the dosage limitation of onvansertib of claims 13-14 and 19, Valsasina discloses compound of formula (I) (AKA, onvansertib ) can be administered orally, in the form of tablets, capsules etc. and at dosage of 45 mg/kg, 60 mg/kg, etc. (See [0035],Table 10-12). Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05.
Regarding the administration limitation of instant claims 15- 20, Valsasina discloses a method of treating or delaying the progression of a proliferative disorder comprising a simultaneous, sequential or separate administration to a subject in need thereof of a therapeutically effective amount of the combination, and one or more active agent, wherein time intervals of administration are chosen such that the effect of combination therapy on the treated disease is larger than the effect which would be obtained by use of only any one of the combination (See [0011], [0032], Tables 1-9, claims 20-21).
Valsasina is silent about onvansertib for inhibiting non-adrenergic contraction of smooth muscle. Pharmacological activities are properties of active agents. “Inhibiting non-adrenergic contraction of a smooth muscle " would naturally flow from Valsasina’s method of treating benign prostatic hyperplasia BPH with onvansertib, since onvansertib is being administered to the same subject suffering benign prostatic hyperplasia BPH as instantly claimed. In other words, even though the prior art is silent regarding "inhibiting contraction of a smooth muscle ...", by practicing the method made obvious by the prior art , one will also be "inhibiting contraction of a smooth muscle ", even though the prior art was not aware of it.
Valsasina is silent about combination with tamsulosin.
A skilled artisan would have known tamsulosin (Flomax®) is an alpha1 adrenoceptor antagonist approved by U.S. Food and Drug Administration (FDA) for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) in 1997. Tamsulosin exhibits selectivity for alpha1 receptors in the human prostate wherein blockade adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH ( See Mechanism of action) (which reads on claim 3 and 5).
Combination therapy is common practice for treating disease/disorder as illustrated by Valsasina. It would have been prima facie obvious for one of ordinary skilled in the art before the effective filing date of instant invention to explore Valsasina’s combination therapy by combining onvansertib with tamsulosin for a method of treating benign prostatic hypertrophy, together with experimentation/optimization(amount of active ingredient, administration route/order, etc.) based on general knowledge of smooth muscle contraction/benign prostate hyperplasia treatment, and arrive at instantly claimed invention with reasonable expectation of success. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846,850, 205 USPQ 1069, 1072 {CCPA 1980) See MPEP 2144.06.
In search for an alternative method of treating benign prostate hyperplasia, a skilled artisan would be motivated to combine onvansertib taught by Valsasina with tamsulosin because tamsulosin is approved by FDA for treating BPH . One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of prostate smooth muscle contraction/benign prostate hyperplasia BPH treatment. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of unexpected result as evidence to the contrary.
Claims 1, 3, 5, 13- 28 are rejected under 35 U.S.C. §103 as being unpatentable over Valsasina et al.( US 2012/0114641 A, Applicant’s IDS dated 06/16/2023), in view of Hennenberg et al.( Frontiers in Physiology 2018, 9:734, “Hennenberg’ 2018”, Applicant’s IDS dated 06/16/2023, doi: 10.3389/fphys.2018.00734, “Inhibition of Prostate Smooth Muscle Contraction by Inhibitors of Polo-Like Kinases”), Fujimori et al.(US 2004/0138241 A1, Applicant’s IDS dated 06/16/2023) and Hennenberg et al. (The Journal Of Urology, 2016, Vol. 195, No. 4S, Supplement, MP44-18, https://doi.org/10.1016/j.juro.2016.02.274, hereafter “Hennenberg ‘2016”, Inhibition Of Smooth Muscle Contraction By The Inhibitor For Cytohesin Family Guanosine Nucleotide Exchange Factors, Secin H3 In The Hyperplastic Human Prostate).
The collective teachings of Valsasina are elaborated in preceding 103 rejection and applied as before. Valsasina teaches treating BPH by administering onvansertib. Valsasina is silent about onvansertib in combination with tamsulosin for inhibiting contraction of smooth muscle in a patient with BPH. A skilled artisan would have known tamsulosin (Flomax®) was approved by FDA for the treatment of benign prostatic hyperplasia (BPH) in 1997. Pharmacological activities are properties of active agents. “Inhibiting contraction of a smooth muscle induced by action potential" would naturally flow from Valsasina’s method of treating benign prostatic hyperplasia BPH with onvansertib, since onvansertib is being administered to the same subjects suffering from benign prostatic hyperplasia BPH. In other words, even though the prior art is silent regarding "inhibiting contraction of a smooth muscle induced by action potential ", by practicing the method made obvious by the prior art , one will also be "inhibiting contraction of a smooth muscle ", even though the prior art was not aware of it.
Further, Hennenberg’ 2018 teaches mechanism/pathways of prostate smooth muscle contraction, e.g. α1-adrenoceptor antagonists, etc. and a possible role of polo-like kinase 1 (PLK1) for smooth muscle contraction outside the lower urinary tract (See Background, Introduction). Hennenberg’ 2018 teaches available drugs for treating LUTS suggestive of BPH improve urinary flow (Qmax) or international prostate symptom scores (IPSS) by not more than 50%(which reads on instant claim 3). Hennenberg’ 2018 teaches variety of Polo-Like Kinase (PLK) inhibitors (e.g. SBE 13, cyclapolin 9, TAK 960, and Ro 3280, etc.) were tested on BPH smooth muscles contraction of human prostate tissues, wherein contractions were induced by electric field stimulation (EFS), endothelin-1, etc. in organ bath(See Abstract, Methods, page 2, left column, Figures 1-7). Hennenberg’ 2018 teaches EFS simulates action potentials, resulting in the release of endogenous neurotransmitters, including norepinephrine. Using the inhibitor for neurotransmitter release, tetrodotoxin, it has been previously demonstrated, that this accounts for two-thirds of EFS-induced contraction in the human prostate( See page 4, right column).
Regarding new claims 22 and 26, Hennenberg’ 2018 teaches the effects of PLK Inhibitors on EFS-induced prostate smooth muscle contractions wherein PLK inhibitors at 100nM, e.g. TAK 960 (100 nM), and Ro 3280 (100 nM) showed significant inhibition activity ( See Abstract,/results, page 5, right column, Figure 4 ). Hennenberg’ 2018 concludes that alpha1-adrenergic smooth muscle contraction in the human prostate can be inhibited by PLK inhibitors. PLK-dependent signaling may be a new pathway, which promotes α1-adrenergic contraction of prostate smooth muscle cells(See Conclusion).
Regarding combination therapy comprising α1-blocker, Fujimori teaches combination therapy comprising α1-blocker and a method of inhibiting endothelin ET-induced (non-adrenergic) contraction due to prostatic cancer and/or benign prostatic hypertrophy with combination comprising α1-blocker (See [0018], [0020], claims 8-11, 14-17). Fujimori teaches dysuria due to benign prostatic hypertrophy is a disease causing urinary dysfunction due to compression by prostate of prostatic urethra accompanying hypertrophy of prostate (mechanical obstruction) or excessive contraction of prostatic smooth muscle (functional obstruction) due to an increase of α1-receptor, etc. (See [0003]).
Regarding claim 3, Fujimori teaches α1-blocker exhibits an improving rate from 40 to 70% in the measurement of urinary flow (See 0016]) . Fujimori explicitly teaches tamsulosin hydrochloride as the α1-blocker that can be used in the combination therapy (See [0025]). Fujimori teaches the activity of tamsulosin hydrochloride, wherein tamsulosin hydrochloride (10 ug/kg i.v.) and combination thereof reduced ET-1 induced pressure (contraction) of prostate tissue (See [0080]-[0084], Figure 11)( which also reads on claim18).
Fujimori teaches combination therapy comprising α1-blocker for inhibition of endothelin-induced contraction in prostatic disease (e.g. benign prostatic hypertrophy) (See claims 2-3, 14-15). Fujimori teaches endothelin ET1 is produced in human epithelial cells and prostatic cells to cause contraction or proliferation of prostatic smooth muscle (See [0010]), and the production of ET-1 is accelerated in prostatic cells of patients with benign prostatic hypertrophy (See [0015]).
Fujimori is silent about tamsulosin inhibiting EFS-induced smooth muscle contraction.
Hennenberg’ 2016 teaches combination of tamsulosin ( 300nM ) with active agent ( Secin H3) for inhibiting EFS-induced prostate smooth muscle contraction(which also reads on instant claims 23 and 27). Hennenberg’ 2016 teaches Secin H3 (30 uM) significantly reduced contractions induced by norepinephrine, phenylephrine, U46619, endothelin-1, and endothelin-3. Hennenberg’ 2016 teaches Secin H3 (30 uM) significantly reduced EFS-induced contractions with similar efficacy as tamsulosin (300 nM) wherein inhibition by secin H3 or by tamsulosin ranged around 50 % at each frequence. Hennenberg’ 2016 teaches combined application of secin H3 plus tamsulosin caused larger inhibition of EFS-induced contractions than tamsulosin alone (p<0.05 at 4-32 Hz for tamsulosin vs. tamsulosin + secin H3), which may offer attractive new possibilities in treatment of male lower urinary tract symptoms (LUTS) ( See e606, left column, Results/ Figure).
Combination therapy is common practice for treating disease/disorder as taught by Valsasina, Fujimori and Hennenberg’ 2016. It would have been obvious for one of ordinary skilled in the art before the effective filing date of instant invention to modify Valsasina’s onvansertib combination by combining onvansertib with an α1-blocker for inhibiting smooth muscle contraction associated with benign prostatic hypertrophy as taught by Fujimori and Hennenberg’ 2016. At the time the invention was made, it was known that onvansertib could be combined with other active agents/drugs in combination therapy for treating benign prostatic hypertrophy BPH as taught by Valsasina. Hennenberg’ 2018 further teaches PLK inhibitor inhibiting prostatic smooth muscle contraction associated with benign prostatic hypertrophy. A skilled artisan would have known tamsulosin (Flomax®) was approved by FDA for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) in 1997. It was also known that α1-blocker( tamsulosin hydrochloride) could be used in combination therapy for inhibiting smooth muscle contraction (ET-induced and EFS-induced) associated with benign prostatic hypertrophy as taught by Fujimori and Hennenberg’ 2016. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful I for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846,850, 205 USPQ 1069, 1072 {CCPA 1980) See MPEP 2144.06.
The skilled artisan would be motivated to combine the teachings of Valsasina, Hennenberg’ 2018, Fujimori and Hennenberg’ 2016 because all teachings are related to treatment associated with benign prostatic hypertrophy/ lower urinary tract symptoms LUTS. Hennenberg’ 2018 further teaches PLK inhibitor inhibiting prostatic smooth muscle contraction induced by EFS, ET, etc. associated with benign prostatic hypertrophy. The modification of Valsasina’s onvansertib combination with tamsulosin hydrochloride taught by Fujimori and Hennenberg’ 2016 , together with experimentation/ optimization(amount of active ingredient, administration route/order, etc.) based on general knowledge of smooth muscle contraction/benign prostate hyperplasia treatment would provide an alternative method of treating benign prostate hyperplasia associated with inhibiting contraction of smooth muscle with combination comprising onvansertib and tamsulosin.
Regarding the amended limitation of synergistic inhibition and claim 18, the limitation is considered as intended function/ treatment outcome which does not necessarily contribute to the structural limitation of method claims. As taught by prior art, both onvansertib (PLK inhibitor) and tamsulosin (α1-blocker ) are useful in treating BPH which is associated with contraction of smooth muscle in prostate cells/or tissue. Hennenberg’ 2018 teaches the effects of PLK Inhibitors on EFS-induced prostate smooth muscle contractions wherein PLK inhibitors at 100nM, e.g. TAK 960 (100 nM), and Ro 3280 (100 nM) showed significant inhibition activity (which reads on instant claims 22 and 26). Hennenberg’ 2016 collectively teaches combination comprising tamsulosin ( 300nM ) for inhibiting EFS-induced smooth muscle contraction wherein combined application caused larger inhibition of EFS-induced contractions than tamsulosin alone (which reads on instant claims 23 and 27). A skilled artisan would reasonably expect 100nM onvansertib in combination with 300nM of tamsulosin inhibit contraction of a smooth muscle more effectively than treatment with onvansertib alone or tamsulosin alone in the absence of evidence to the contrary. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of prostate smooth muscle contraction/benign prostate hyperplasia. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of unexpected result as evidence to the contrary.
Claims 1, 3, 5, 13-20, 23-24 and 27- 28 are rejected under 35 U.S.C. §103 as being unpatentable over Valsasina et al.( US 2012/0114641 A1), in view of Chueh et al. (European Journal of Pharmacology 1996, 305(1-3), 177-180, Applicant’s IDS dated 06/16/2023, “Inhibition by tamsulosin of tension responses of human hyperplastic prostate to electrical field stimulation”) and Hennenberg et al.(The Prostate 77:697-707, 2017, “Hennenberg’ 2017”, Applicant’s IDS dated 06/16/2023, “Non-Adrenergic, Tamsulosin-Insensitive Smooth Muscle Contraction Is Sufficient to Replace α1-Adrenergic Tension in the Human Prostate”).
The collective teachings of Valsasina are elaborated in preceding 103 rejection and applied as before. Valsasina teaches treating BPH by administering onvansertib. Valsasina is silent about onvansertib in combination with tamsulosin for inhibiting contraction of smooth muscle in a patient with BPH.
A skilled artisan would have known tamsulosin (Flomax®) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) in 1997. Chueh teaches tamsulosin is a selective and potent α1-blocker and has potent antagonistic effect on human prostate in in-vitro functional study with externally applied noradrenaline (See abstract, page 177, right column; page 180, left column). Chueh teaches benign prostatic hyperplasia (BPH) refers to the progressive enlargement of prostate associated with α1-adrenoceptors(See introduction, page 177).
Regarding instant claim 5, 23 and 27, Chueh evaluates activity of tamsulosin ( 0.1nM, 1nM) on muscle contraction of human hyperplastic prostate in response to electrical field stimulation and showed that tamsulosin exhibited greater potency against field stimulation (EFS)-induced contraction compared to that against phenylephrine-induced contraction (See Figure 1; page 180, left column). Please note EFS-induced contraction read on the amended limitation “induced by action potential”.
Hennenberg’ 2017 teaches non-adrenergic contraction of prostate smooth muscle induced by a variety of agents /mediators, e.g. endothelin-1(See page 697, abstract, Results; page 699, right column; Fig. 2). Hennenberg’ 2017 teaches activation of purinergic receptors by ATP may induce smooth muscle contractions in different organs of the lower urinary tract (See page 705, left column and right column). Hennenberg’ 2017 teaches α1- adrenoceptor antagonists (α1-blockers) are widely used for treatment of male LUTS suggestive of BPH to improve voiding symptoms and urinary flow by relaxation of prostate smooth muscle, and α1-blocker represent the gold standard of medical LUTS therapy in men, as they may reduce international prostate symptom scores (IPSS) by 30–50%, and enhance urinary flow (Qmax) up to15–40% (See introduction). Hennenberg’ 2017 teaches tamsulosin (300nM) significantly inhibits noradrenaline-induced and dopamine-induced smooth muscle contraction. Hennenberg’ 2017 teaches tamsulosin (300nM ) were further evaluated on a variety of non-adrenergic contraction of prostate smooth muscle induced by a variety of agents /mediators, e.g. endothelin-1(See Figure 1)(which read on instant claims 23 and 27).
Combination therapy is common practice for treating disease/disorder as taught by Valsasina. It would have been obvious for one of ordinary skilled in the art before the effective filing date of instant invention to modify Valsasina’s onvansertib combination by combining onvansertib with tamsulosin for inhibiting non-adrenergic contraction (EFS-induced) associated with benign prostatic hypertrophy as taught by Chueh, and further explore more non-adrenergic contractions induced by other agents (e.g. endothelin-induced) as taught by Hennenberg’ 2017. At the time the invention was made, it was known that onvansertib could be combined with other active agents/drugs in combination therapy for treating benign prostatic hypertrophy BPH as taught by Valsasina. It was also known that tamsulosin(300nM) exhibits potent activity for inhibiting non-adrenergic contraction (EFS-induced) associated with benign prostatic hypertrophy as taught by Chueh and Hennenberg’ 2017 . "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful I for the same purpose, in order to form a third composition to be used for the very same purpose .... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846,850, 205 USPQ 1069, 1072 {CCPA 1980) See MPEP 2144.06.
A skilled artisan would be motivated to combine the teachings of Valsasina, Chueh and Hennenberg’ 2017 because all teachings are directed to treatment associated with benign prostatic hypertrophy. Chueh and Hennenberg’ 2017 further teach benign prostatic hypertrophy is a disease associated with contraction of prostatic smooth muscle. The modification of Valsasina combination with α1-blocker (e.g. tamsulosin) taught by Chueh and Hennenberg’ 2017, together with experimentation/optimization(amount of active ingredient, administration route/order, etc.) based on general knowledge of prostate smooth muscle contraction/benign prostate hyperplasia treatment would provide an alternative method of treating benign prostate hyperplasia associated with inhibiting EFS-induced contraction of smooth muscle with combination comprising onvansertib and tamsulosin.
Regarding new limitation of synergistic inhibition and claim 18, the limitations are considered as intended function/ treatment outcome which does not necessarily contribute to the structural limitation of method claims. As taught by prior art, both onvansertib and α1-blocker are useful in treating BPH which is associated with contraction of smooth muscle in prostate cells/or tissue. A person of ordinary skilled in the art would reasonably expect onvansertib in combination with α1-blocker inhibit the contraction of a smooth muscle more effectively than treatment with onvansertib alone or the α1-blocker alone in the absence of evidence to the contrary.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of prostate smooth muscle contraction/benign prostate hyperplasia. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of unexpected result as evidence to the contrary.
Response to Arguments
Based on the calculation by Bliss model, Applicant argues “ synergistic inhibition of the contraction that is at least 13% greater than the inhibition from the corresponding treatment with onvansertib or the α1- blocker alone ”(Remarks, page 7-9).
Response: Applicant’s argument about the “synergistic inhibition” is fully considered, but they are NOT persuasive to overcome 35 USC 103 rejection as elaborated above.
The examiner does not dispute combination of onvansertib (34% individually) and tamsulosin (48% individually) is calculated to have 66 % inhibition based on Bliss model (Remarks, page 8). However, Applicant’s calculation of 79 % observed inhibition is confusing and inaccurate , wherein the calculation of "add-on" inhibition”, “marginal inhibition” “relative inhibition” and “total inhibition” are confusing and contradictory since Applicant explicitly states “ Additive effects are not simple arithmetic sums”. As disclosed by instant Spec : “The effect of the add-on of onvansertib was similar using tamsulosin and silodosin (59± 11.5% inhibition of 32 Fz-induced contraction by onvansertib compared to tamsulosin alone” ( page 17, lines 8-10), “The effect of the add-on of a1-blocker was similar using tamsulosin and silodosin (68±12.2% inhibition of 32 Fz- induced contraction by tamsulosin compared to onvansertib alone” (page 17, lines 15-17). Applicant argues “add-on inhibition” relative to single-agent inhibition as illustrated in Fig 5. However, A POSA reading the inhibition value in Fig 5A and 5B would interpret the inhibition bar as total inhibition, NOT as relative inhibition to tamsulosin or onvansertib, respectively. The total inhibition bar of tamsulosin(300nM)/ onvansertib (100nM) combination in Fig 5A is more in line with the add-on inhibition of 59 % or 68%, which is close to the calculated 66% of combination inhibition.
Hennenberg’ 2018 teaches the effects of PLK Inhibitors on EFS-induced prostate smooth muscle contractions wherein PLK inhibitors at 100nM, e.g. TAK 960 (100 nM), and Ro 3280 (100 nM) showed significant inhibition activity. Hennenberg’ 2016 collectively teaches combination comprising tamsulosin ( 300nM ) for inhibiting EFS-induced smooth muscle contraction wherein combined application caused larger inhibition of EFS-induced contractions than tamsulosin alone. Hennenberg’ 2017 also teaches 300 nM tamsulosin was evaluated for variety of smooth muscle contraction induced by variety of agent( noradrenaline, dopamine, ET-1, etc.). Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05. A POSA would be motivated to evaluate combination of 100 nM onvansertib in combination with 300 nM tamsulosin in EFS-induced smooth muscle contraction and reasonably expect the combination would provide additive effect.
As stated in MPEP 716.02(d): “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”. It’s noted only 100nM onvansertib combined with 300nM tamsulosin are tested, instant specification does not disclose additive activity exists for different combination of onvansertib and tamsulosin at different concentrations for inhibiting prostate smooth muscle contraction induced by other neurotransmitter associated with action potential. There is no comparation of onvansertib/tamsulosin combination at different concentration to establish the criticality of combination of 100 nM onvansertib with 300 nM tamsulosin. The dosage of onvansertib and tamsulosin recited in instant claims 21-28 are based on in-vitro assay which might not necessarily translate into therapeutically effective dosage regimen in patients having BPH.
The Applicant tries to establish novelty over the prior art by claiming a different mechanism of combining onvansertib and tamsulosin. However, the alleged in-vitro synergy on inhibiting 32 Hz EFS-induced prostate smooth muscle contraction by 100 nM onvansertib in combination with 300nM tamsulosin might not translate into efficacy in a patient having BPH. As disclosed in instant Spec ( page 22, lines 9-22), it’s only speculation that onvansertib may be effective in vivo. There is no in-vivo test or clinical experiment/ evidence that explicitly show treating BPH is exclusively due to inhibiting non-adrenergic contraction of smooth muscle indued by action potential or inhibiting adrenergic contraction of smooth muscle. There is no experiment/evidence that show inhibiting action potential induced smooth muscle contraction works better than inhibiting adrenergic smooth muscle contraction in treating BPH. An ordinary skilled in the art would not know whether the efficacy of treating BPH with combination of onvansertib with tamsulosin is the result of inhibiting adrenergic smooth muscle contraction or non-adrenergic smooth muscle contraction, or through both pathways, or through other pathways.
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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/L.M./Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
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