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
Claims 1-14 are pending in the instant application.
Claims 1-14 are being examined on their merits herein.
Priority
The instant application is a Continuation of U.S. Patent Application 18/530,663, filed on 6 December 2023, now abandoned, which is a Continuation of U.S. Patent Application 18/297,853, filed on 10 April 2023, now abandoned, which is a Continuation of U.S. Patent Application 17/096,528, filed on 12 November 2020, now abandoned, which is a Continuation of U.S. Patent Application 15/811,973, filed on 14 November 2017, now U.S. Patent 10,864,215, which is a Continuation of International Patent Application PCT/US2016/032779, filed on 16 May 2016, which claims priority from U.S. provisional Patent Application No. 62/313,476, filed on 25 March 2016, U.S. provisional Patent Application No. 62/265,641 filed on 10 December 2015 and U.S. provisional Patent Application No. 62/162,534, filed on 15 May 2015.
Information Disclosure Statement
No information disclosure statement (IDS) has been submitted.
Claim Objection
Claim 1 is objected to because the recitation “having CAS Registry No. 371943-05-4” is unnecessary and it does not add clarity to the claim.
Claim 14 (which depends on claim 1) is objected to because the recitation “a second agent that inhibits the PI3K/AKT pathway” seems to imply that there is a first agent that does the same, it inhibits the PI3K/AKT pathway; yet claim 1 does not recite that the compound inhibits the PI3K/AKT pathway. The examiner suggests that claim 14 could recite –further comprising administering to the subject a second agent, wherein the second agent inhibits the PI3K/AKT pathway and is present in an amount […]--.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over Hayakawa et al. (Bioorganic & Medicinal Chemistry 2006, 14, 6847-6858, cited in PTO-892), in view of Kurek et al. (The American Journal of Human Genetics 2012, 90, 1108-1115, cited in PTO-892).
Hayakawa (Bioorganic & Medicinal Chemistry 2006, 14, 6847-6858) teaches compound 15e
PNG
media_image1.png
159
174
media_image1.png
Greyscale
(page 6851, last compound in Table 4), which is the very compound in the instant claims, as a selective PI3K p110a inhibitor.
Hayakawa teaches that thieno[3,2-d]pyrimidine compound 15e above is a potent inhibitor of p110a activity in vitro with IC50 = 2 nM (Table 4), with a high selectivity profile over other isoforms of PI3K and over other protein kinases (Table 5, page 6851, right column, first paragraph).
PNG
media_image2.png
150
300
media_image2.png
Greyscale
Hayakawa teaches that compound 15e is a highly selective inhibitor for p110a among other kinases, making it the first example of a p110a-selective PI3K inhibitor (page 6851, right column, last paragraph).
Hayakawa teaches that the PI3KCA gene, which encodes PI3K p110a, is amplified and overexpressed in a number of cancers, and is also mutated in a spectrum of cancers, and that inhibitors of p110a are potential cancer therapeutic agents. Hayakawa teaches that compound 15e above is an effective antiproliferation agent against A375 cells (malignant melanoma cells, cell-based assay IC50 = 0.58 mM, Table 4).
Hayakawa does not teach that compound 15e is effective to treat a venous malformation, as in the instant claims.
Kurek et al. (The American Journal of Human Genetics 2012, 90, 1108-1115) teaches somatic activating mutations in PIK3CA cause CLOVES syndrome. Kurek teaches that CLOVES is congenital lipomatous asymmetric overgrowth of the trunk with lymphatic, capillary, venous and combined type vascular malformations (page 1108, left column, second paragraph). Kurek teaches (page 1110, Table 1) that PIK3CA mutations are present in venous malformations in all the patients with CLOVES syndrome tested.
Kurek teaches (Table 2) PIK3CA mutations in patients with CLOVES syndrome and venous malformation. Kurek specifically teaches (Table 2) c.1624G>A (p.Glu542Lys), which results in PIK3CA E542K mutation, and c.1258T>C (p.Cys420Arg), which results in PIK3CA C420R mutation, which are mutations of instant claims 2-4, in patients with CLOVES syndrome and venous malformation.
Kurek teaches (Table 1) p.His1047Arg, p.Glu542Lys, p.Cys420Arg, synonyms H1047R, E542K, and C420R mutations, which are mutations of instant claims 2-4, in patients with CLOVES syndrome and venous malformation.
Kurek teaches (Figure 3) that the vascular malformation is located within the skin, as in instant claim 5.
Kurek teaches (page 1110, right column, first paragraph) that PI3KCA encodes the 110-kD catalytic alpha subunit of PI3K.
Kurek teaches (page 1112, left column, last paragraph, right column, first paragraph) that similar to CLOVES, Klippel-Trenaunay syndrome (KTS) exhibits venous anomalies and overgrowth, and KTS may also result from mutations in the PI3K-AKT pathway. Kurek identifies PI3KCA mutations in KTS patients.
Kurek teaches (page 1112, last paragraph) that activating mutations are the cause of CLOVES syndrome; the same activating mutations have been detected in several types of cancer and pharmacologic inhibitors of PIK3CA are developed for treatment of these tumors. Importantly, Kurek teaches that the same inhibitors might have therapeutic applications for individuals with CLOVES syndrome or other overgrowth anomalies that are also the result of somatic activating mutations of PIK3CA.
Kurek does not teach a method of treating a venous malformation with the compound in the instant claims.
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to combine the teachings of Hayakawa and Kurek to arrive at the instantly claimed method.
The person of ordinary skill in the art at the time the invention was made would have been motivated to administer a selective PI3K p110a inhibitor which is compound 15e taught by Hayakawa, to a patient in need thereof, to treat a venous malformation because
Hayakawa teaches that compound 15e is a highly selective inhibitor for p110a PI3K, and Hayakawa teaches that selective inhibitors for p110a PI3K are potential therapeutic agents in cancers characterized by amplified, overexpressed or mutated PI3KCA gene (PI3KCA being the gene which encodes PI3K p110a);
Kurek teaches that activating PIK3CA mutations are present in venous malformations in patients with CLOVES syndrome; and
Kurek teaches that pharmacologic inhibitors of PIK3CA developed for treatment of cancer may have therapeutic applications for individuals with CLOVES syndrome or other overgrowth anomalies that are also the result of somatic activating mutations of PIK3CA.
Thus, the person of ordinary skill in the art would have been motivated to evaluate selective PI3K p110a inhibitor which is compound 15e taught by Hayakawa, in a method of treating venous malformation in patients with CLOVES, with the expectation that compound 15e taught by Hayakawa will inhibit p110a PI3K and its mutations and will be effective to treat patients with vascular malformations carrying amplified, overexpressed or mutated PI3KCA, such as patients with CLOVES and activating PIK3CA mutations.
The person of ordinary skill in the art would have evaluated selective PI3K p110a inhibitor which is compound 15e taught by Hayakawa, in a method of treating venous malformation in a subject suffering from CLOVES having an activating mutation of PIK3CA such as H1047R, E542K, and C420R (mutations taught by Kurek in CLOVES patients), with the expectation that said compound, which was originally discovered as inhibitor of PIK3CA for treatment of cancer, will have therapeutic application for subjects with CLOVES syndrome or other overgrowth anomalies that are also the result of somatic activating mutations of PIK3CA.
Further, the person of ordinary skill in the art would have administered selective PI3K p110a inhibitor compound 15e taught by Hayakawa, systemically or locally, topically, orally, or parenterally, as in instant claims 8-13, because choosing a route of administration of a drug, in order to optimize therapeutic effect, is well within the skills of the artisan.
With respect to claim 6, the person of ordinary skill in the art would have administered selective PI3K p110a inhibitor compound 15e taught by Hayakawa, to patients with venous malformation who are high risk for surgical treatment, because administering a therapeutic agent as an alternative to high risk surgery in a method of treatment is well within the skill of the artisan.
With respect to claim 14, the person of ordinary skill in the art would have combined selective PI3K p110a inhibitor compound 15e taught by Hayakawa and a second agent that inhibits the PI3K/AKT pathway, with the expectation that the resulting combination will have therapeutic effect. Since all compounds for co-administration herein are known to be PI3K/AKT inhibitors, it is considered prima facie obvious to co-administer them in a method used for the same purpose. At least additive therapeutic effects would have been reasonably expected. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980).
As such, claims 1-14 are rejected as prima facie obvious.
Claims 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over Hayakawa et al. (Bioorganic & Medicinal Chemistry 2006, 14, 6847-6858, cited in PTO-892), in view of Fritsch et al. (Mol Cancer Ther 2014, 13, 1117-1129, cited in PTO-892), Luks et al. (J. Pediatr 2015, 166 (4), 1048-1054, published April 2015, cited in PTO-892) and Kurek et al. (The American Journal of Human Genetics 2012, 90, 1108-1115, cited in PTO-892).
Hayakawa (Bioorganic & Medicinal Chemistry 2006, 14, 6847-6858) teaches compound 15e
PNG
media_image1.png
159
174
media_image1.png
Greyscale
(page 6851, last compound in Table 4), which is the very compound in the instant claims, as a selective PI3K p110a inhibitor.
Hayakawa teaches that thieno[3,2-d]pyrimidine compound 15e above is a potent inhibitor of p110a activity in vitro with IC50 = 2 nM (Table 4), with a high selectivity profile over other isoforms of PI3K and over other protein kinases (Table 5, page 6851, right column, first paragraph).
PNG
media_image2.png
150
300
media_image2.png
Greyscale
Hayakawa teaches that compound 15e is a highly selective inhibitor for p110a among other kinases, making it the first example of a p110a-selective PI3K inhibitor (page 6851, right column, last paragraph).
Hayakawa teaches that the PI3KCA gene, which encodes PI3K p110a, is amplified and overexpressed in a number of cancers, and is also mutated in a spectrum of cancers, and that inhibitors of p110a are potential cancer therapeutic agents. Hayakawa teaches that compound 15e above is an effective antiproliferation agent against A375 cells (malignant melanoma cells, cell-based assay IC50 = 0.58 mM, Table 4).
Hayakawa does not teach that compound 15e is effective to treat a venous malformation, as in the instant claims.
Fritsch et al. (Mol Cancer Ther 2014, 13, 1117-1129) teaches (page 1118, left column, third paragraph) BYL-719 as a selective PI3Ka inhibitor potent against the most common somatic mutations of PI3Ka.
Fritsch teaches that BYL-719 has significant dose-dependent antitumor efficacy in mice bearing PIK3CA-dependent tumor xenograft models.
Fritsch teaches that PIK3CA mutant cell lines are selectively sensitive to BYL719 (page 1125). Fritsch teaches 88% response rate to BYL719 in PIK3CA mutant mice (page 1124, last paragraph).
Fritsch teaches that BYL-719 potently inhibits the two most common PIK3CA somatic mutations H1047R and E545K (Table 1, page 1119, right column, third paragraph).
Luks et al. (J. Pediatr 2015, 166 (4), 1048-1054, published April 2015) teach lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. Luks teaches (page 1049, left column, first paragraph) that most patients suffering from isolated lymphatic malformations (LM), patients with fibro-adipose vascular anomaly (FAVA), patients with CLOVES syndrome (which has a venous malformation component), and patients with Klippel-Trenaunay syndrome (KTS) have somatic PIK3CA mutations, and that 5 recurrent mutations, namely C420R, E542K, E545K, H1047R, H1047L (page 1049, right column, under ddPCR), which are mutations of instant claim 4, account for the majority of cases.
Luks teaches (page 1053, right column, second paragraph) that 80% of affected tissue from patients with isolated LM, CLOVES, KTS or FAVA contained 1 of the 5 mutations above; for samples that did not have the 5 recurrent PIK3CA mutations, high throughput sequencing identified additional disease-causing PIK3CA mutations in another 8% of the samples.
Importantly, Luks teaches that PIK3CA inhibitors are currently in development as cancer therapeutics. Luks teaches (page 1053, right column, second paragraph) that these inhibitors may also benefit patients with LM, CLOVES, KTS and FAVA.
Kurek et al. (The American Journal of Human Genetics 2012, 90, 1108-1115) teaches somatic activating mutations in PIK3CA cause CLOVES syndrome. Kurek teaches that CLOVES is congenital lipomatous asymmetric overgrowth of the trunk with lymphatic, capillary, venous and combined type vascular malformations (page 1108, left column, second paragraph). Kurek teaches (page 1110, Table 1) that PIK3CA mutations are present in venous malformations in all the patients with CLOVES syndrome tested.
Kurek teaches (Table 2) PIK3CA mutations in patients with CLOVES syndrome and venous malformation. Kurek specifically teaches (Table 2) c.1624G>A (p.Glu542Lys), which results in PIK3CA E542K mutation, and c.1258T>C (p.Cys420Arg), which results in PIK3CA C420R mutation, which are mutations of instant claims 2-4, in patients with CLOVES syndrome and venous malformation.
Kurek teaches (Table 1) p.His1047Arg, p.Glu542Lys, p.Cys420Arg, synonyms H1047R, E542K, and C420R mutations, which are mutations of instant claims 2-4, in patients with CLOVES syndrome and venous malformation.
Kurek teaches (Figure 3) that the vascular malformation is located within the skin, as in instant claim 5.
Kurek teaches (page 1112, left column, last paragraph, right column, first paragraph) that similar to CLOVES, Klippel-Trenaunay syndrome (KTS) exhibits venous anomalies and overgrowth, and KTS may also result from mutations in the PI3K-AKT pathway. Kurek identifies PI3KCA mutations in KTS patients.
Kurek teaches (page 1112, last paragraph) that activating mutations are the cause of CLOVES syndrome; the same activating mutations have been detected in several types of cancer and pharmacologic inhibitors of PIK3CA are developed for treatment of these tumors. Importantly, Kurek teaches that the same inhibitors might have therapeutic applications for individuals with CLOVES syndrome or other overgrowth anomalies that are also the result of somatic activating mutations of PIK3CA.
Kurek does not teach a method of treating a venous malformation with the compound in the instant claims.
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to combine the teachings of Hayakawa, Fritsch, Luks and Kurek to arrive at the instantly claimed method.
The person of ordinary skill in the art at the time the invention was made would have been motivated to administer a selective PI3K p110a inhibitor which is compound 15e taught by Hayakawa, to a patient in need thereof, to treat a venous malformation in a subject having an activating mutation of PIK3CA, because
Hayakawa teaches that compound 15e is a highly selective inhibitor for p110a PI3K, and Hayakawa teaches that selective inhibitors for p110a PI3K are potential therapeutic agents in cancers characterized by amplified, overexpressed or mutated PI3KCA gene (PI3KCA being the gene which encodes PI3K p110a);
Fritsch teaches that selective PI3K p110a inhibitor BYL719 showed efficacy in PIK3CA mutants and in wild-type cell lines, and BYL-719 potently inhibits the two most common PIK3CA mutations H1047R and E545K;
Luks and Kurek teaches that activating PIK3CA mutations such as E545K, and H1047R are present in venous malformations in patients with CLOVES syndrome; and
Kurek teaches that pharmacologic inhibitors of PIK3CA developed for treatment of cancer may have therapeutic applications for individuals with CLOVES syndrome or other overgrowth anomalies that are also the result of somatic activating mutations of PIK3CA.
The person of ordinary skill in the art would have been motivated to evaluate compound 15e taught by Hayakawa in a method of treating venous malformation in patients with CLOVES, with the expectation that compound 15e taught by Hayakawa, which is a selective PI3K p110a inhibitor, can be used interchangeably with BYL719 to inhibit p110a PI3K and its mutations and will be effective to treat patients with vascular malformations carrying amplified, overexpressed or mutated PI3KCA, such as patients with CLOVES and activating PIK3CA mutations.
The person of ordinary skill in the art would have evaluated selective PI3K p110a inhibitor which is compound 15e taught by Hayakawa, in a method of treating venous malformation in a subject suffering from CLOVES having an activating mutation of PIK3CA such as H1047R, E542K, and C420R (mutations taught by Kurek and Luks in CLOVES patients), with the expectation that said compound, which was originally discovered as inhibitor of PIK3CA for treatment of cancer, will have therapeutic application for subjects with CLOVES syndrome or other overgrowth anomalies that are also the result of somatic activating mutations of PIK3CA.
Further, the person of ordinary skill in the art would have administered selective PI3K p110a inhibitor compound 15e taught by Hayakawa, systemically or locally, topically, orally, or parenterally, as in instant claims 8-13, because choosing a route of administration of a drug, in order to optimize therapeutic effect, is well within the skills of the artisan.
With respect to claim 6, the person of ordinary skill in the art would have administered selective PI3K p110a inhibitor compound 15e taught by Hayakawa, in patients with venous malformation who are high risk for surgical treatment, because administering a therapeutic agent as an alternative to high risk surgery in a method of treatment is well within the skill of the artisan.
With respect to claim 14, the person of ordinary skill in the art would have combined selective PI3K p110a inhibitor compound 15e taught by Hayakawa and a second agent that inhibits the PI3K/AKT pathway, with the expectation that the resulting combination will have therapeutic effect. Since all compounds for co-administration herein are known to be PI3K/AKT inhibitors, it is considered prima facie obvious to co-administer them in a method used for the same purpose. At least additive therapeutic effects would have been reasonably expected. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980).
As such, claims 1-14 are rejected as prima facie obvious.
Conclusion
Claims 1-14 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY S. LUNDGREN can be reached at (571)272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/IRINA NEAGU/Primary Examiner, Art Unit 1629
Prosecution Insights