A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/1/2025 has been entered.
DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Amendment after Final office action filed on 8/1/2025 is acknowledged.
3. Claims filed on 8/1/2025 is acknowledged.
4. Claims 2, 5-17, 22-28, 30-35 and 37 have been cancelled.
5. Claims 1, 3, 4, 18-21, 29, 36 and 38-41 are pending in this application.
6. Claims 21, 29, 36 and 41 remain withdrawn from consideration as being drawn to non-elected species.
7. Applicant elected without traverse of Group 1 (claims 1, 3, 4, 12, 13, 18-21, 29 and 35-37) and elected a stapled ICL PTAIB with the sequence Ac-LTF8EYWAQ L$AAAAAa-NH2 (SEQ ID NO: 14) as species of ICL PTAIB; diffuse interstitial pontine glioma as species of pediatric cancer; and immunotherapy as species of additional therapeutic regimen in the reply filed on 4/26/2024.
Restriction requirement was deemed proper and made FINAL in the previous office actions. Group 1 is drawn to a method of treating a pediatric cancer in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of an internally cross-linked (ICL) p53 transactivation domain-based inhibitor peptide (PTAIB), wherein the pediatric cancer comprises: detectable wild-type p53 or detectable functional p53, wherein the ICL PTAIB is Ac-LTF8EYWAQL$AAAAAa-NH2 (SEQ ID NO: 14), and wherein Ac is acetyl; 8 is Alpha-Me R8-octenyl-alanine olefin amino acid connected by an all-carbon crosslinker comprising one double bond to $, $ is alpha-Me S5-pentenyl-alanine olefin amino acid connected by an all-carbon crosslinker comprising one double bond to 8, and a is D-alanine. A search was conducted on the elected species; and diffuse interstitial pontine glioma as the elected species of pediatric cancer appears to be free of prior art. However, prior art was found for a stapled ICL PTAIB with the sequence Ac-LTF8EYWAQL$AAAAAa-NH2 (SEQ ID NO: 14) as the elected species of ICL PTAIB; and immunotherapy as the elected species of additional therapeutic regimen. A search was extended to the genus in claim 1; and prior art was found. Claims 21, 29, 36 and 41 remain withdrawn from consideration as being drawn to non-elected species. Claims 1, 3, 4, 18-20 and 38-40 are examined on the merits in this office action.
Declaration under 37 CFR 1.132
8. The Examiner would like to point out the Declaration of Loren D. Walensky under 37 CFR 1.132 filed on 8/1/2025 is identical to the Declaration of Loren D. Walensky under 37 CFR 1.132 filed on 1/17/2025, which has been addressed in Section 13 of the Final office action dated 3/3/2025.
9. The Declaration of Michelle Monje under 37 CFR 1.132 filed on 8/1/2025 is insufficient to prove diffuse interstitial pontine glioma as the elected species of pediatric cancer is an error and there is no such cancer known as pediatric diffuse interstitial pontine glioma because:
First, the Examiner would like to point out one of ordinary skilled in the art would not expect interstitial is a typo of intrinsic.
Second, the Examiner understands that both Applicant and Dr. Monje have provided various documents to indicate that there are some confusions between diffuse interstitial pontine glioma and diffuse intrinsic pontine glioma. However, in the instant case, based on the filed documents, it appears to the Examiner that such confusion/error only happens when citing other references, such as several documents from Moleculin (filed by Applicant), Bailey et al (filed by Applicant) and many others. And such confusion/error is most likely due to both diffuse interstitial pontine glioma and diffuse intrinsic pontine glioma have the same acronym DIPG, because the confusion/error in all these documents from different authors is always between diffuse interstitial pontine glioma and diffuse intrinsic pontine glioma.
Third, based on search performed by the Examiner, there is such cancer known as pediatric diffuse interstitial pontine glioma and/or diffuse interstitial pontine glioma. Kenyon et al (Case Reports and Images in Oncology, 2020, 1, pages 1-5) explicitly teach treating a 9-year old male patient suffering diffuse interstitial pontine glioma; and a 9-year old female patient suffering diffuse interstitial pontine glioma, for example, pages 3-4, Table 2. The existence of diffuse interstitial pontine glioma and/or pediatric diffuse interstitial pontine glioma is further confirmed by the Novogen news release document (2014, enclosed pages 1-5, from https://www.prnewswire.com/news-releases/novogen-announces-breakthrough-discovery-in-the-treatment-of-melanoma-300010254.html, see for example, page 2, the 1st paragraph), the PTC Therapeutic Clinical Study Protocol document (from https://cdn.clinicaltrials.gov/large-docs/55/NCT05269355/Prot_000.pdf, 2023, enclosed pages 1-92, see for example, page 26, the 4th paragraph), the Brain Stem Glioma document (from https://qureclinic.com/wp-content/uploads/2024/09/BSG-09202019.pdf, accessed 2025, enclosed pages 1-2, see for example, page 1, the 2nd paragraph), and many others. And in the instant case, there is no evidence to indicate diffuse interstitial pontine glioma and/or pediatric diffuse interstitial pontine glioma discussed in all these references are mistake, and it should be diffuse intrinsic pontine glioma.
Taken all these together, there is insufficient evidence to indicate diffuse interstitial pontine glioma as the elected species of pediatric cancer, disclosed in instant specification and recited in claims 36 and 37 filed on 4/26/2024 is an obvious error, and should have been diffuse intrinsic pontine glioma. And there is insufficient evidence to indicate there is no such cancer known as diffuse interstitial pontine glioma and/or pediatric diffuse interstitial pontine glioma.
The Kenyon et al, the Novogen news release document, the PTC Therapeutic Clinical Study Protocol document and the Brain Stem Glioma document are cited only for the purpose of rebutting Applicant's arguments, therefore, they are not cited as prior art references.
10. The Declaration of Steven DuBois under 37 CFR 1.132 filed on 8/1/2025 is insufficient to overcome the rejection to instant claims 1, 3, 4, 18-20 and 38-40 under 35 U.S.C. 103 as set forth in Section 16 below because:
First, with regards to the toxicity of the HDM2 inhibitor RG7112 observed in adult patients or in animal study, as stated in the previous office action, it appears to the Examiner that Applicant is applying the standard for drug approvement at FDA to examination of patent application at USPTO. However, examination of patent application at USPTO is based on patent laws, rules and guidance provided in MPEP. Drug toxicity is not a criterial for examining patent application.
Second, the Examiner would like to point out that Applicant fails to provide any evidence and/or reasoning to indicate that the toxicity of the HDM2 inhibitor RG7112 observed in adult patient or in animal study would apply to every single HDM2 inhibitor and/or every single compound targeting both HDM2 and HDMX. It is unclear to the Examiner how and/or why, based on the toxicity of a single HDM2 inhibitor, one of ordinary skilled in the art would expect every single HDM2 inhibitor and/or every single compound targeting both HDM2 and HDMX would be toxic to all patients. Further clarification is required.
Third, the Examiner would like to point out that as discussed in the Declaration of Loren D. Walensky under 37 CFR 1.132 filed on 1/17/2025, pediatric patient is not the same as adult patient, such as the level of toxicity, how to calculate the dosage, the metabolism of the drugs and so on. Therefore, in the instant case, considering the state of art regarding the known difference between pediatric patient and adult patient, one of ordinary skilled in the art would not expect that the toxicity of a single HDM2 inhibitor observed in adult patient would apply to every single HDM2 inhibitor and/or every single compound targeting both HDM2 and HDMX in pediatric patient.
Fourth, the Examiner would like to bring Applicant’s attention to MPEP § 716.02, which sets up the guideline on allegation of unexpected results, such as “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims”. And in the instant case, the closest prior art is ATSP-7041 taught in Chang et al.
Fifth, as stated in the previous office action, the Examiner would like to point out that as stated in Section 16 below, Walensky et al explicitly teach treating cancer by targeting both HDM2 and HDMX; and synergistic anti-tumor activity of SAH-p53-8 and nutlin-3 (a HDM2 modulating agent), for example, Figures 9, 10 and 11E. Therefore, in the instant case, in view of the teachings of Walensky et al as a whole, one of ordinary skilled in the art would understand and reasonably expect an agent that targets both HDMX and HDM2 would be beneficial and effective in the treatment of cancer that comprises detectable functional p53. And as stated in Section 16 below, Carol et al explicitly teach that p53 mutations are less prevalent in pediatric cancer; and a larger proportion of pediatric patients may benefit from pharmacological unleashing of the wild-type p53 protein. Pishas et al explicilty teach approximately 90% of Ewing sarcoma, an aggressive pediatric malignancy, retains a functional wild-type p53, which makes it an ideal candidate for use of p53 activators as a novel systemic therapeutic approach. Therefore, in view of the combined teachings of Walensky et al, Carol et al and Pishas et al, one of ordinary skilled in the art would understand and reasonably expect an agent that targets both HDMX and HDM2 would be beneficial and effective in the treatment of pediatric cancer, such as pediatric Ewing sarcoma. Furthermore, it is well known in the art that the two p53 suppressors, MDM2 and MDMX, which are highly expressed in tumors, often work together as one complex to inactivate p53 by mediating its ubiquitination and degradation as well as to directly inhibit p53 transcriptional activity in a feedback fashion; and many investigators have now been looking for dual inhibitors of MDM2 and MDMX in order to activate p53 in cancer therapy, as discussed in Shadfan et al (Transl Cancer Res., 2012, 1, pages 88-99, filed with IDS, see for example, Conclusions), Zhang et al (Chapter 16 Targeting p53-MDM2-MDMX Loop for Cancer Therapy, S.P. Deb and S. Deb (eds.), Mutant p53 and MDM2 in Cancer, Subcellular Biochemistry 85, 2014, pages 281-319, filed with IDS, see for example, page 283, Figure 16.1) and many others. In addition, using dual inhibitors of MDM2 and MDMX in order to unleash wild-type and/or functional p53 from the inhibitory complex and activate p53 in cancer therapy is well known in the cancer therapy art, as disclosed in Zhang et al (Chapter 16 Targeting p53-MDM2-MDMX Loop for Cancer Therapy, S.P. Deb and S. Deb (eds.), Mutant p53 and MDM2 in Cancer, Subcellular Biochemistry 85, 2014, pages 281-319, filed with IDS, see for example, pages 285-288, Table 16.1) and many others. And in the instant case, as stated in Section 16 below, effectively and successfully treating cancer with the dual inhibitor of MDM2 (synonym of HDM2) and MDMX (synonym of HDMX) ATSP-7041 (identical to ALRN-7041 of instant SEQ ID NO: 5) is explicitly taught in the cited Chang et al reference.
Taken all these together, there is no reason for one of ordinary skilled in the art to expect every single HDM2 inhibitor and/or every single compound targeting both HDM2 and HDMX would be toxic to all patients. And there is insufficient evidence to indicate ALRN-6924 being safe in pediatric subject tested in Applicant’s study is unexpected.
The Shadfan et al and Zhang et al references are cited only for the purpose of rebutting Applicant's arguments, therefore, they are not cited as prior art references.
Maintained Objections
11. The amendment to the specification filed on 1/17/2025 remains 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: Frist, as stated in Section 9 above, there is insufficient evidence to indicate diffuse interstitial pontine glioma as the elected species of pediatric cancer, disclosed in instant specification and recited in claims 36 and 37 filed on 4/26/2024 is an obvious error, and should have been diffuse intrinsic pontine glioma. Second, the Examiner understands that the Title of reference 47 disclosed in instant specification recites the term “diffuse intrinsic pontine glioma”. However, the Examiner would like to point out that reference 47 is not incorporated by reference in instant specification. Furthermore, it appears to the Examiner that Applicant is assuming any reference cited in instant specification is part of Applicant’s invention. However, Applicant fails to explain on what such assumption is based. Further clarification is required.
Please note: The specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification (see MPEP § 608.01).
Response to Applicant's Arguments
12. Applicant argues that ““diffuse interstitial pontine glioma” was an obvious error and should have instead been “diffuse intrinsic pontine glioma”” by citing various documents and the Declaration of Michelle Monje under 37 CFR 1.132 filed on 8/1/2025.
13. Applicant's arguments have been fully considered but have not been found persuasive.
Applicant’s arguments about diffuse interstitial pontine glioma and the Declaration of Michelle Monje under 37 CFR 1.132 filed on 8/1/2025 have been addressed in Section 9 above.
Therefore, the objection is deemed proper and is hereby maintained.
Maintained Rejections
Claim Rejections - 35 U.S.C. § 103
14. 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 of this title, 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.
15. 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.
16. Claims 1, 3, 4, 18-20 and 38-40 remain rejected under 35 U.S.C. 103 as being unpatentable over Walensky et al (US 2014/0018302 A1, filed with IDS) in view of Carol et al (Pediatr Blood Cancer, 2013, 60, pages 633-641, filed with IDS), Pishas et al (Clin Cancer Res, 2011, 17, pages 494-504, filed with IDS), Chang et al (PNAS, 2013, pages E3445-E3454, filed with IDS) and Guerlavais et al (US 8927500 B2, filed with IDS).
The instant claims 1, 3, 4, 18-20 and 38-40 are drawn to a method of treating a pediatric cancer in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of an internally cross-linked (ICL) p53 transactivation domain-based inhibitor peptide (PTAIB), wherein the pediatric cancer comprises: detectable wild-type p53 or detectable functional p53, wherein the ICL PTAIB is Ac-LTF8EYWAQL$AAAAAa-NH2 (SEQ ID NO: 14), and wherein Ac is acetyl; 8 is Alpha-Me R8-octenyl-alanine olefin amino acid connected by an all-carbon crosslinker comprising one double bond to $, $ is alpha-Me S5-pentenyl-alanine olefin amino acid connected by an all-carbon crosslinker comprising one double bond to 8, and a is D-alanine.
Walensky et al, throughout the patent, teach a method of treating cancer in a human subject in need thereof, wherein the method comprises administering to the human subject with cancer a HDMX modulating agent and/or a HDM2 modulating agent, thereby increasing p53 activity in the cell; wherein the HDMX modulating agent can be SAH-p53-8 (a ICL PTAIB) that binds to both HDMX and HDM2; and wherein the cancer comprises detectable functional p53, for example, page 1, paragraph [0008] to page 2, paragraph [0011]; Figure 1C; page 2, paragraphs [0014]-[0018]; page 21, paragraph [0289]; and page 25, Example 2. It meets the limitation of human subject recited in instant claim 1. Walensky et al further teach the cancer comprises detectable HDMX which forms a complex with the detectable functional p53, for example, Figure 11; and page 2, paragraphs [0011] and [0017]. Walensky et al also teach the HDMX modulating agent such as SAH-p53-8 can be used in combination with chemotherapy, radiotherapy, and antibody therapy, for example, page 22, paragraph [0299]. It reads on immunotherapy as the elected species of additional therapeutic regimen; and meets the limitations of instant claims 18 and 19. Furthermore, Walensky et al teach the cancer can be Ewing’s tumor, for example, page 23, paragraph [0307]. In addition, Walensky et al teach treating cancer by targeting both HDM2 and HDMX; and synergistic anti-tumor activity of SAH-p53-8 and nutlin-3 (a HDM2 modulating agent), for example, Figures 9, 10 and 11E.
The difference between the reference and instant claims 1, 3, 4, 18-20 and 38-40 is that the reference does not explicitly teach a stapled ICL PTAIB with the sequence Ac-LTF8EYWAQL$AAAAAa-NH2 (SEQ ID NO: 14) as the elected species of ICL PTAIB and recited in instant claim 1; and the cancer is a pediatric cancer recited in instant claims 1, 20 and 38-40.
However, Carol et al teach that p53 mutations are less prevalent in pediatric cancer; and a larger proportion of pediatric patients may benefit from pharmacological unleashing of the wild-type p53 protein, for example, page 633, the 3rd paragraph in “Introduction”. Carol et al further teach treating pediatric cancer with RG7112, a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis, for example, page 633, Background, Results and Conclusions; page 635, Table I; pages 635-636, Section “RG7112 In Vivo Testing”; and page 637, Table II. Carol et al also teach Ewing sarcoma as one of the pediatric cancers comprising detectable wild-type p53 that forms complex with MDM2 (synonym of HDM2) and overexpression of MDM2 (synonym of HDM2) in Ewing sarcoma; and RG7112 induces tumor regression in Ewing sarcoma xenograft, for example, page 635, Table I; page 637, Table II; and page 638, left column, the 1st paragraph and Figure 2.
Furthermore, Pishas et al teach approximately 90% of Ewing sarcoma, an aggressive pediatric malignancy, retains a functional wild-type p53, which makes it an ideal candidate for use of p53 activators as a novel systemic therapeutic approach, for example, page 494, Abstract; and page 495, Section “Translation Relevance”. Pishas et al further teach treating Ewing sarcoma cells with Nutlin-3a, a small cis-imidazoline molecule antagonist of MDM2 (synonym of HDM2), that disrupts the p53–MDM2 interaction by blocking the p53-binding pocket of MDM2, for example, page 495, left column, the 2nd paragraph; and Figures 1 and 2. Pishas et al also teach Nutlin-3a augments the cytotoxic effects of chemotherapeutic agents in Ewing sarcoma cells, for example, page 500, Figure 3. Furthermore, Pishas et al teach MDM4 (synonym of HDMX) is overexpressed in the majority of wild-type p53 Ewing sarcoma cell lines; and Nutlin-3a synergizes with an MDM4 antagonist, therefore, targeted inhibition of both MDM2 and MDM4 may result in a more robust activation of the p53 pathway in the Ewing sarcoma family of tumors (ESFTs), for example, Figure 5A; Figure 6; and page 501, right column, the 2nd paragraph.
In addition, Chang et al, throughout the literature, teach a stapled peptide ATSP-7041 as a highly potent and selective dual inhibitor of MDM2 (synonym of HDM2) and MDMX (synonym of HDMX) that exhibits robust p53-dependent tumor growth suppression in MDM2/MDMX-overexpressing xenograft cancer models, with a high correlation to on-target pharmacodynamic activity, and possesses favorable pharmacokinetic and tissue distribution properties, in comparison to the original p53-derived stapled peptide SAH-p53-8, for example, Abstract; and Figures 1 and 3-8. Chang et al further teach ATSP-7041 is a staple peptide consisting of the amino acid sequence Ac-LTFR8EYWAQCbaS5SAA-NH2, wherein R8 at position 4 with all hydrocarbon staple to S5 at position 11, and having the chemical structure:
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, for example, page E3448, Figure 1A. Chang et al also teach ATSP-7041 provides a unique therapeutic lead molecule to be interrogated in a broad diversity of p53-positive tumors driven by MDM2 and MDMX, for example, page E3453, right column, the last paragraph.
And, Guerlavais et al, throughout the patent, teach that similar to ATSP-7041 taught in Chang et al, the stapled peptide SP331 (SEQ ID NO: 340) with the structure
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is a highly potent and selective dual inhibitor of MDM2 (synonym of HDM2) and MDMX (synonym of HDMX); and can be used for the treatment of diseases and disorders, such as cancers or other disorders characterized by a low level or low activity of a p53 protein or high level of activity of a MDM2 and/or MDMX protein, including Ewing's tumor and many others, for example, Abstract; column 58, line 58 to column 59, line 11; columns 75 and 76, Table 1; columns 91-92, Table 1c; column 134, Table 4; and claim 42. The staple peptide SP331 (SEQ ID NO: 340) in Guerlavais et al is identical to instant SEQ ID NO: 14 recited in instant claim 1. It reads on a stapled ICL PTAIB with the sequence Ac-LTF8EYWAQL$AAAAAa-NH2 (SEQ ID NO: 14) as the elected species of ICL PTAIB.
Therefore, it would have been obvious to one of ordinary skilled in the art to combine the teachings of Walensky et al, Carol et al, Pishas et al, Chang et al and Guerlavais et al to develop a method of treating pediatric Ewing sarcoma in a human subject in need thereof, wherein the method comprises administering to the human subject the stapled peptide SP331 (SEQ ID NO: 340, identical to instant SEQ ID NO: 14) as a potent and selective dual inhibitor of MDM2 (synonym of HDM2) and MDMX (synonym of HDMX), and wherein the method further comprises treating the human subject with antibody therapy.
One of ordinary skilled in the art would have been motivated to combine the teachings of Walensky et al, Carol et al, Pishas et al, Chang et al and Guerlavais et al to develop a method of treating pediatric Ewing sarcoma in a human subject in need thereof, wherein the method comprises administering to the human subject the stapled peptide SP331 (SEQ ID NO: 340, identical to instant SEQ ID NO: 14) as a potent and selective dual inhibitor of MDM2 (synonym of HDM2) and MDMX (synonym of HDMX), and wherein the method further comprises treating the human subject with antibody therapy, because Carol et al teach that p53 mutations are less prevalent in pediatric cancer; and a larger proportion of pediatric patients may benefit from pharmacological unleashing of the wild-type p53 protein. Carol et al further teach Ewing sarcoma as one of the pediatric cancers comprising detectable wild-type p53 that forms complex with overexpressed MDM2 in Ewing sarcoma; and RG7112 (a selective inhibitor of p53-MDM2 binding that frees p53 from negative control) induces tumor regression in Ewing sarcoma xenograft. Pishas et al teach approximately 90% of Ewing sarcoma, an aggressive pediatric malignancy, retains a functional wild-type p53, which makes it an ideal candidate for use of p53 activators as a novel systemic therapeutic approach. Pishas et al further teach treating Ewing sarcoma cells with Nutlin-3a, a small cis-imidazoline molecule antagonist of MDM2 (synonym of HDM2), that disrupts the p53–MDM2 interaction by blocking the p53-binding pocket of MDM2. Pishas et al also teach MDM4 (synonym of HDMX) is overexpressed in the majority of wild-type p53 Ewing sarcoma cell lines; and Nutlin-3a synergizes with an MDM4 antagonist, therefore, targeted inhibition of both MDM2 and MDM4 may result in a more robust activation of the p53 pathway in the Ewing sarcoma family of tumors (ESFTs). And Chang et al teach a stapled peptide ATSP-7041 (identical to ALRN-7041 of instant SEQ ID NO: 5) as a highly potent and selective dual inhibitor of MDM2 (synonym of HDM2) and MDMX (synonym of HDMX) that exhibits robust p53-dependent tumor growth suppression in MDM2/MDMX-overexpressing xenograft cancer models, with a high correlation to on-target pharmacodynamic activity, and possesses favorable pharmacokinetic and tissue distribution properties, in comparison to the original p53-derived stapled peptide SAH-p53-8. Guerlavais et al, throughout the patent, teach that similar to ATSP-7041 taught in Chang et al, the stapled peptide SP331 (SEQ ID NO: 340, identical to instant SEQ ID NO: 14) is a highly potent and selective dual inhibitor of MDM2 (synonym of HDM2) and MDMX (synonym of HDMX); and can be used for the treatment of diseases and disorders, such as cancers or other disorders characterized by a low level or low activity of a p53 protein or high level of activity of a MDM2 and/or MDMX protein, including Ewing's tumor and many others.
A person of ordinary skilled in the art would have reasonable expectation of success in combining the teachings of Walensky et al, Carol et al, Pishas et al, Chang et al and Guerlavais et al to develop a method of treating pediatric Ewing sarcoma in a human subject in need thereof, wherein the method comprises administering to the human subject the stapled peptide SP331 (SEQ ID NO: 340, identical to instant SEQ ID NO: 14) as a potent and selective dual inhibitor of MDM2 (synonym of HDM2) and MDMX (synonym of HDMX), and wherein the method further comprises treating the human subject with antibody therapy.
Response to Applicant's Arguments
17. Applicant argues that “One of skill in the art would not have specifically selected SP331 out of a long list of cross-linked peptidomimetic macrocycles disclosed by Guerlavais.” Applicant further argues that “One of skill in the art would not have been motivated to apply a dual HDM2/HDMX inhibitor to the treatment of pediatric cancers.” Applicant also argues that “No reasonable expectation that a drug useful for treatment of adult cancers would have been successful for treating pediatric cancers.”
18. Applicant's arguments have been fully considered but have not been found persuasive.
In response to Applicant's arguments about instant rejection, the Examiner would like to point out that instant claims 1, 3, 4, 18-20 and 38-40 are rejected under pre-AIA 35 U.S.C. 103(a) (obviousness type), and the rejection is based on the combined teachings of Walensky et al, Carol et al, Pishas et al, Chang et al and Guerlavais et al; therefore, it is not necessary for each of the cited references to teach all the limitations of instant claims. Furthermore, the Examiner would like to point out that the MPEP states "One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references…" (see MPEP § 2145 IV).
In response to Applicant's arguments that “One of skill in the art would not have specifically selected SP331 out of a long list of cross-linked peptidomimetic macrocycles disclosed by Guerlavais”: The Examiner understands that Guerlavais et al teach more than one selective dual inhibitors of MDM2 (synonym of HDM2) and MDMX (synonym of HDMX). However, in the instant case, Guerlavais et al explicilty teach the stapled peptide SP331 (SEQ ID NO: 340) is a highly potent and selective dual inhibitor of MDM2 (synonym of HDM2) and MDMX (synonym of HDMX); and it is one of the limited/finite numbers (24 recited in the claims in Guerlavais et al) of dual inhibitor tested in the working examples and recited in the claims in Guerlavais et al. Therefore, in the instant case, in view of the teachings of Guerlavais et al as a whole, it would have been obvious to one of ordinary skilled in the art, and/or one of ordinary skilled in the art would have been motivated to select and/or try the stapled peptide SP331 out of the 24 dual inhibitors in Guerlavais et al; and in view of the combined teachings of the cited prior art references as set forth in Section 16 above to develop a method of treating pediatric Ewing sarcoma in a human subject in need thereof. Furthermore, the Examiner would like to point out that the fact that there are more than one highly potent and selective dual inhibitor of MDM2 (synonym of HDM2) and MDMX (synonym of HDMX) in Guerlavais et al does not render any of them unobvious.
In response to Applicant’s arguments that “One of skill in the art would not have been motivated to apply a dual HDM2/HDMX inhibitor to the treatment of pediatric cancers”:
First, with regards to Applicant’s arguments based on the HDM2 inhibitor RG7112 observed in adult patient or in animal study and the arguments presented in the Declaration of Steven DuBois under 37 CFR 1.132 filed on 8/1/2025, these have been addressed in Section 10 above.
Second, the Examiner would like to point out the in the instant case, it is unclear to the Examiner how and/or why the decision in Takeda Chemical Industries, Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350 (Fed. Cir. 2007) should apply to instant rejection. In the instant case, Applicant fails to provide any evidence and/or reasoning to indicate the fact pattern of Takeda Chemical Industries, Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350 (Fed. Cir. 2007) is similar and/or identical to the fact pattern of instant rejection. Further clarification is required.
In response to Applicant’s arguments that that “No reasonable expectation that a drug useful for treatment of adult cancers would have been successful for treating pediatric cancers”: The Examiner understands that pediatric patient is not the same as adult patient, such as the level of toxicity, how to calculate the dosage, the metabolism of the drugs and so on, as discussed in the Declaration of Loren D. Walensky under 37 CFR 1.132 filed on 1/17/2025. However, in the instant case, the Examiner would like to point out that considering the state of art regarding the difference between pediatric patient and adult patient, one of ordinary skilled in the art would have been motivated to optimize the dosage of the drug for effectively treating pediatric patient. Furthermore, as stated in the previous office action, the Examiner would like to point out that as explicitly stated in Rahal et al (Am J Cancer Res, 2018, 8, pages 1356-1386, filed with IDS), "Adult cancers on average exhibit substantially higher mutational burdens compared with the vast majority of childhood tumors" (see for example, page 1356, Abstract). Rahal et al further teach that understanding the mutational changes provides opportune windows for more effective and personalized treatments tailored to mutational profiles of each cancer patient, for example, page 1364, left column, Section "Precision medicine of pediatric and adult cancer"; and pages 1364-1366, Section "Personalized therapy". And in the instant case, as stated in Section 16 above, Carol et al explicitly teach that p53 mutations are less prevalent in pediatric cancer; and a larger proportion of pediatric patients may benefit from pharmacological unleashing of the wild-type p53 protein. Pishas et al explicilty teach approximately 90% of Ewing sarcoma, an aggressive pediatric malignancy, retains a functional wild-type p53, which makes it an ideal candidate for use of p53 activators as a novel systemic therapeutic approach. Therefore, considering the state of art regarding dual inhibitors of MDM2 and MDMX to activate p53 in cancer therapy as discussed in Section 10 above, and in view of the teachings of Rahal et al above and the combined teachings of Walensky et al, Carol et al and Pishas et al as set forth in Section 16 above, one of ordinary skilled in the art would understand and reasonably expect that dual inhibitors of MDM2 and MDMX would be effective in treating pediatric cancer, including pediatric Ewing sarcoma patient. In addition, as explicitly stated in the MedicineNet document (2020, pages 1-6, filed with IDS, NPL No. 182 in the IDS filed on 7/25/2023), the cure rate of adult cancer, such as adult leukemia, is significantly lower than that of pediatric cancer (see for example, page 1, the 2nd and 3rd paragraphs). Taken all these together, considering the state of art regarding treating pediatric patient, including pediatric cancers, and the state of art regarding dual inhibitors of MDM2 and MDMX to activate p53 in cancer therapy, and in view of the combined teachings of the cited prior art references as set forth in Section 16 above, a person of ordinary skilled in the art would have reasonable expectation of success in developing the method recited in instant claims 1, 3, 4, 18-20 and 38-40. Furthermore, with regards to the expectation of success, the MPEP states: “Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.” (see MPEP § 2145).
Taken all these together, the rejection is deemed proper and is hereby maintained.
The Rahal et al and the MedicineNet document are cited only for the purpose of rebutting Applicant's arguments, therefore, they are not cited as prior art references.
Obviousness Double Patenting
19. 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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
20. Claims 1, 3, 4, 18-20 and 38-40 remain rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-25 of US patent 8889632 B2 in view of Walensky et al (US 2014/0018302 A1, filed with IDS), Carol et al (Pediatr Blood Cancer, 2013, 60, pages 633-641, filed with IDS), Pishas et al (Clin Cancer Res, 2011, 17, pages 494-504, filed with IDS), Chang et al (PNAS, 2013, pages E3445-E3454, filed with IDS) and Guerlavais et al (US 8927500 B2, filed with IDS).
21. Instant claims 1, 3, 4, 18-20 and 38-40 are drawn to a method of treating a pediatric cancer in a human subject in need thereof, wherein the method comprises administering to the human subject a therapeutically effective amount of an internally cross-linked (ICL) p53 transactivation domain-based inhibitor peptide (PTAIB), wherein the pediatric cancer comprises: detectable wild-type p53 or detectable functional p53, wherein the ICL PTAIB is Ac-LTF8EYWAQL$AAAAAa-NH2 (SEQ ID NO: 14), and wherein Ac is acetyl; 8 is Alpha-Me R8-octenyl-alanine olefin amino acid connected by an all-carbon crosslinker comprising one double bond to $, $ is alpha-Me S5-pentenyl-alanine olefin amino acid connected by an all-carbon crosslinker comprising one double bond to 8, and a is D-alanine.
22. Claims 1-25 of US patent 8889632 B2 are drawn to a modified peptide of Formula (I) that binds to HDMX and HDM2.
23. The difference between claims 1-25 of US patent 8889632 B25 and instant claims 1, 3, 4, 18-20 and 38-40 is that claims 1-25 of US patent 8889632 B2 does not teach the method recited in instant claims 1, 3, 4, 18-20 and 38-40.
However, in view of the combined teachings of Walensky et al, Carol et al, Pishas et al, Chang et al and Guerlavais et al as set forth in Section 16 above, it would have been obvious to one of ordinary skilled in the art to modify the peptide of Formula (I) recited in claims 1-25 of US patent 8889632 B2 and apply it in a method of treating pediatric Ewing sarcoma in a human subject and develop the method recited in instant claims 1, 3, 4, 18-20 and 38-40.
24. For the same/similar reasoning and/or rational as the rejection set forth in Sections 20-23 above, instant claims 1, 3, 4, 18-20 and 38-40 remain rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-15 of US patent 9527896 B2, claims 1-17 of US patent 10202431 B2, claims 1-29 of US patent 10822374 B2, and claims 1-18 of US patent 12480163 B2 (issued patent of US application No. 17/260824); and further in view of the combined teachings of Walensky et al (US 2014/0018302 A1, filed with IDS), Carol et al (Pediatr Blood Cancer, 2013, 60, pages 633-641, filed with IDS), Pishas et al (Clin Cancer Res, 2011, 17, pages 494-504, filed with IDS), Chang et al (PNAS, 2013, pages E3445-E3454, filed with IDS) and Guerlavais et al (US 8927500 B2, filed with IDS) as set forth in Section 16 above.
25. For the same/similar reasoning and/or rational as the rejection set forth in Sections 20-23 above, instant claims 1, 3, 4, 18-20 and 38-40 remain provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 5, 23, 32-35, 37, 45, 50, 52-54, 61, 69-75, 78 and 79 of co-pending application No. 17/920503; and further in view of the combined teachings of Walensky et al (US 2014/0018302 A1, filed with IDS), Carol et al (Pediatr Blood Cancer, 2013, 60, pages 633-641, filed with IDS), Pishas et al (Clin Cancer Res, 2011, 17, pages 494-504, filed with IDS), Chang et al (PNAS, 2013, pages E3445-E3454, filed with IDS) and Guerlavais et al (US 8927500 B2, filed with IDS) as set forth in Section 16 above.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Response to Applicant's Arguments
26. With regards to the ODP rejections over claims of the various US patents, Applicant argues that “As described in the remarks in response to the rejection under 35 U.S.C. § 103, there is no reasonable expectation of success in arriving at the claimed invention and the claimed invention is further associated with unexpected results.”
With regards to the provisional ODP rejections over claims of the co-pending Applications, Applicant argues that both co-pending application No. 17/260824 and co-pending application No. 17/920503 are later filed applications.
27. Applicant's arguments have been fully considered but have not been found persuasive.
With regards to Applicant’s arguments about the ODP rejections over claims of the various US patents, these have been addressed in Sections 10 and 18 above.
With regards to Applicant’s arguments about the provisional ODP rejections over claims of the co-pending Applications, in the instant case, first, US application No. 17/260824 has been issued as US patent 12480163 B2. Second, the provisional ODP rejections are not the only remaining rejection in the current office action.
Taken all these together, until a proper terminal disclaimer is filed and approved by the Office, these double patenting rejections are maintained.
Conclusion
All claims are drawn to the same invention claimed in the application prior to the entry of the submission under 37 CFR 1.114 and could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 extension fee 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.
No claim is allowed.
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/LI N KOMATSU/Primary Examiner, Art Unit 1658