DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment and Arguments
2. Claims 1, 16, 17, 19, 21, 22, 24-30, 41, 43 and 58-68 are pending.
Claims 22, 27-29, 41 and 43, drawn to non-elected species and non-elected inventions are withdrawn from examination.
Claims 7, 56 and 57 have been cancelled.
Claims 1, 30 and 59 have been amended.
Claims 61-68 have been added.
Claims 1, 16, 17, 19, 21, 24-26, 30, 41, 43 and 58-68 are examined on the merits with species (mutation): Y772dupYVMA.
3. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Withdrawn Grounds of Rejection
Claim Rejections - 35 USC § 112
4. The rejection of claims 1, 16, 17, 19, 21, 24-26, 30, 58 and 60 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of the amendments to claim 1. Claims 7, 56 and 57 have been cancelled.
Double Patenting
5. The provisional rejection of claims 1 and 30 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 6, 10-13, 19, 23, 24, 28 and 29 of copending Application No. 17/600,017 (filed September 29, 2021) is withdrawn. Claim 7 has been cancelled.
6. The provisional rejection of claims 1 and 30 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7, 11-14, 16-21, 23 and 24 of copending Application No. 17/042,012 (filed September 25, 2020) is withdrawn. Claim 7 has been cancelled.
New Grounds of Objection
Specification
7. The disclosure is objected to because of the following informalities: the specification cites different units for poziotinib, wherein the dosage is cited as milligram (mg) on page 3, section 0010; page 4, section 0013; and page 32, section 00106. However, poziotinib is also cited as milligram/kilogram (mg/kg), see page 7, section 0029; page 9, section 0036; page 18, section 0068; section 00107, page 36, section 00118; and page 37, section 00119. Applicant is requested to review the entire disclosure for similar informalities. Applicant should select one manner of citation consistent throughout the specification and claims.
Correction is required.
Claim Objections
8. Claims 59, 64-66 and 68 are objected to because of the following informalities: claim 59 has been amended to recite the dosage of poziotinib in milligram/kilogram (mg/kg), as well as new claim 61. However, additional new claims 64-66 and 68 recite the dosage of the tyrosine kinase inhibitor, poziotinib in the measure of milligram (mg). Applicant is requested to review all claims for similar informalities. Applicant should select one manner of citation consistent throughout the specification and claims.
Correction is required.
New and Maintained Grounds of Rejection
Claim Rejections - 35 USC § 102
9. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
10. Claim(s) 1, 16, 17, 19, 21, 24 and 62-68 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by ClinicalTrials.gov ID NCT03429101 (first posted February 12, 2018/ IDS reference C1 submitted June 16, 2023) as evidenced by Bon et al. (Cancer Science 115(7): 2147-2158, May 7, 2024). ClinicalTrials.gov ID NCT03429101 teaches treating women with advanced or metastatic HER2 positive breast cancer, see pages 2, 3 and 6. The women were treated with a quinazolinamine-based tyrosine kinase inhibitor (TKI), poziotinib in combination with trastuzumab emtansine (T-DM1), see title; and pages 2-5. As evidenced by Bon, exon 20 insertion mutation, Y772_A775dupYVMA occurs in HER2 breast cancers, see paragraph (para.) bridging pages 2149 and 2150; and Figure 2(B) on page 2150.
The T-DM1 was administered once a day within a 21-day cycle, see page 3, Brief Summary; and page 4, Detailed Description. The standard dose of T-DM1 was 3.6 mg/kg IV, see page 3, last para.; and page 4, 1st and 5th paragraphs (paras.). The daily dose of poziotinib was 8 mg/day, see page 4, 1st paragraph of the Detailed Description.
Claim Rejections - 35 USC § 103
11. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
12. 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.
13. The rejection of claim(s) 1, 16, 17, 19, 21, 24-26, 30, 59, 60 and new claims 61-68 under 35 U.S.C. 103 as being unpatentable over Kris et al. (Annals of Oncology 26:1421-1427, July 2015)/ IDS reference C13 submitted June 16, 2023), and further in view of ClinicalTrials.gov ID NCT03429101 (first posted February 12, 2018/ IDS reference C1 submitted June 16, 2023) and Koga et al. (Lung Cancer 126:72-79, published online October 17, 2018/ IDS reference C63 submitted September 6, 2024) is maintained and made. Claims 7, 56 and 57 have been cancelled.
Initially, Applicant states as amended claim 1 “recites a method of treating a HER2 mutant cancer by administering a daily dose of poziotinib during a course of treatment of the subject and administering an effective amount of T-DM1 as a single dose to the subject during the course of treatment of the subject, wherein the HER2 mutant cancer comprises one or more mutations selected from the group consisting of [mutations]”, see Remarks submitted February 13, 2016, page 8, 2nd paragraph (para).; page 9, 2nd para.; and page 10, 1st para.
Applicant also states each reference is “…silent regarding any amount of poziotinib at any dosage, let alone administering [it]…in combination with a single dose T-DMI”, see page 10, 1st para. Furthermore, Applicant alleges none of the cited prior art teaches administering T-DMI as a single dose during the course of treatment and administering an effective amount of poziotinib in combination with a single dose of T-DMI, see page 10 of the Remarks, 1st full para.
Applicant asserts the alleged surprising teachings of their claimed invention, see Remarks, para. bridging pages 8 and 9; and page 10, 2nd para.
Applicant concludes arguments stating the teachings of the prior art references and states a person having ordinary skill in the art (POSA) would not be motivated to combine the cited references as they fail individually or in combination of to render independent claim 1 obvious, see Remarks, page 10, paragraphs (paras.) 1 and 2.
Applicant’s arguments and points of view have been carefully reviewed and considered. They are not found persuasive.
Applicant’s independent claim 1 is silent as to the dosage unit, amount of both, poziotinib and T-DMI.
Kris teaches the quinazolinamine-based tyrosine kinase inhibitor was administered once-a-day, a single dose to patients with HER2-mutant tumors with mutations within exon 20, see page 1422, 2nd column (col.), 1st sentence. The Trials teaches women with advanced or metastatic HER2 positive breast cancer are treated with a daily dose of poziotinib in combination with T-DMI on day 1 of each 21-day cycle, see pages 2 and 3. Koga teaches “[p]oziotinib showed the most potent activity against HER2 exon 20 mutations”, see Abstract on page 72.
Moreover, it would not be outside the scope of the skilled artisan to substitute the tyrosine kinase inhibitor (TKI), dacomitinib of Kris with the TKI, poziotinib of the Trials and Koga. It is obvious to those skilled in the art to substitute one known equivalent for another. See In re Omeprazole Patent Litigation, 483 F.3d 1364, 1374 (Fed. Cir. 2007) (“[T]his court finds no . . . error in [the] conclusion that it would have been obvious to one skilled in the art to substitute one ARC [alkaline reactive compound] for another.”). It is art known at least nine TKIs do exhibit activity for HER2 mutations, see entire Koga document.
As noted in the last Action mailed August 13, 2025, “[t]he modification of the primary reference, in light of the secondary references is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213 USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious.”, see para. bridging pages 10 and 11.
And while Applicant’s arguments include terms, “surprisingly”, and “surprising”, Applicant has not presented any scientific evidence, nor declaration or affidavit to show that the results would have been unexpected to one of ordinary skill in the art and would dissuade the Office from the combination of references. Hence, the rejection is maintained and made for the reasons of record, the analysis and reasoning set forth herein.
Kris teaches treating “…adults with pathologically confirmed stage IIIB or IV lung adenocarcinomas” in addition to “HER2 mutations including exon 20 insertions, deletions, and point mutations in intra- or extracellular domains”, see Background, Patients…segment, and Results spanning pages 1421 and 1422; patients…segment spanning columns 1 and 2 on page 1422. “HER2 mutations included exon 20 insertions, deletions, and point mutations in intra- or extracellular domains.”, see page 1422, patients…segment in column (col.) 1; and sentence bridging pages 1424 and 1425. “The specific aberrations detected in the 26 patients with HER2 mutations are detailed in Table 1 [on page 1423]. Thirteen tumors harbored identical 12-bp exon 20 insertions [A775_G776insYVMA, alternative nomenclature p.Y772_A775dup(c.2313_2324dup)]. There were four 9-bp insertions and three 3-bp insertions.”, page 1422, column 2, last two sentences.
The adults were treated with a quinazolinamine-based tyrosine kinase inhibitor (TKI), dacomitinib (PF-00299804), see page 1422, Conclusions and entire 2nd col. The dacomitinib was administered once-a-day, see page 1422, 1st sentence in col 2.
Kris does not teach the additional administration of a HER antibody-drug conjugate that is trastuzumab emtansine (T-DM1) in a single dose of about 10 mg/kg and within a range from 2 mg/kg to about 3 mg/kg. Kris also does not teach the quinazolinamine-based TKI is poziotinib at a dosage range from about 2 mg/kg to about 3 mg/kg and a range from about 5mg to about 25mg.
However, ClinicalTrials.gov ID NCT03429101 teaches treating women with advanced or metastatic HER2 positive breast cancer, see pages 2, 3 and 6. The women were treated with a quinazolinamine-based tyrosine kinase inhibitor (TKI), poziotinib in combination with trastuzumab emtansine (T-DM1), see title; and pages 2-5. The T-DM1 was administered once a day within a 21-day cycle, see page 3, Brief Summary; and page 4, Detailed Description. The standard dose of T-DM1 was 3.6 mg/kg IV, see page 3, last para.; and page 4, 1st and 5th paragraphs (paras.). The daily dose of poziotinib was 8 mg/day, see page 4, 1st paragraph of the Detailed Description.
Koga teaches poziotinib has “…the most potent activity against HER2 exon 20 mutations”, including point mutations, C805S, YVMA as well as mutations listed in claims 17, 19 and 21, see page Abstract on page 72; page 76, 2nd column, 1st full paragraph; Fig. B, C on page 77; page 78, column 1, 1st full and last paragraphs; and Supplementary Figures 1 and 2. Koga further teaches the implementation of additional TKIs, afatinib and neratinib, see page 72, Abstract; segment 2.3 Reagents on page 73; page 76, 2nd column, 1st full para.; and Table 1 on page 77.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the dacomitinib TKI of Kris with the poziotinib TKI of the Trials and Koga, see all three references. One of ordinary skill in the art would have been motivated by the teachings in the Trials and in particular, Koga that “[p]oziotinib showed the most potent activity against HER2 exon mutations.”, see the Koga abstract.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treatments of Kris, the Clinical trial and Koga to arrive at the claimed invention because all the references report combining therapeutics for targeted HER2 treatment, see all three references in their entireties. One of ordinary skill in the art would have been motivated by the teachings in the documents that targeted therapeutic combinatorial compositions are easily and successfully administered to HER2-mutant or amplified tumors and yield successful antitumor activity in particular to HER2 exon 20 mutations, see all references and in particular, Kris and Koga.
It would been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treatments of Kris, the Clinical trial and Koga to arrive at the effective amount, single dose of T-DMI of about 10mg/kg and range of poziotinib at 2.5 mg/kg and range from 5 mg to 25 mg, see all three references in their entireties. One of ordinary skill in the art would have been motivated by the teachings in the documents that a therapeutic component, T-DMI and poziotinib within the combinatorial treatment modality is easily and successfully administered with a reasonable expectation of success by teachings well known and noted herein that dosages of any pharmaceutical composition may be adjusted and optimized. One of ordinary skill in the art has been provided the general guidance and motivation to modify any of the two components of the successful combination of anti-cancer agents in light of the targeted treatment taught in all the documents and in particular the ClinicalTrials.
14. The rejection of claim(s) 1, 16, 17, 19, 21, 24-26, 30, 58-60 and new claims 61-68 under 35 U.S.C. 103 as being unpatentable over Kris et al. (Annals of Oncology 26:1421-1427, July 2015)/ IDS reference C13 submitted June 16, 2023), and further in view of ClinicalTrials.gov ID NCT03429101 (first posted February 12, 2018/ IDS reference C1 submitted June 16, 2023), Morimura et al. (Biochemical and Biophysical Research Communications 488: 596-602, available online 17 May 2017) and Koga et al. (Lung Cancer 126:72-79, published online October 17, 2018/ IDS reference C63 submitted September 6, 2024) is maintained and made. Claims 7, 56 and 57 have been cancelled.
Applicant incorporates the arguments and comments from the first cited pending 103 into the Remarks for the instant rejection, see Remarks submitted February 13, 2026, page 11, 1st paragraph (para.).
In addition, Applicant states the teachings of Morimura and asserts “similar to Kris and Koga, Morimura is likewise silent regarding administering any amount of poziotinib at any dosage, let alone administering an effective amount of poziotinib in combination with a single dose T-DM1 during the course of treatment, as required by independent claim 1, as amended… the cited references Kris, the '101 trial, Koga, and Morimura, individually or in combination, fail to render independent claim 1, and the claims dependent therefrom, obvious.”, see page 11, 2nd para.
Initially, Applicant states as amended claim 1 “recites a method of treating a HER2 mutant cancer by administering a daily dose of poziotinib during a course of treatment of the subject and administering an effective amount of T-DM1 as a single dose to the subject during the course of treatment of the subject, wherein the HER2 mutant cancer comprises one or more mutations selected from the group consisting of [mutations]”, see Remarks submitted February 13, 2016, page 8, 2nd paragraph (para).; page 9, 2nd para.; and page 10, 1st para.
Applicant also states each reference is “…silent regarding any amount of poziotinib at any dosage, let alone administering [it]…in combination with a single dose T-DMI”, see page 10, 1st para. Furthermore, Applicant alleges none of the cited prior art teaches administering T-DMI as a single dose during the course of treatment and administering an effective amount of poziotinib in combination with a single dose of T-DMI, see page 10 of the Remarks, 1st full para.
Applicant asserts the alleged surprising teachings of their claimed invention, see Remarks, para. bridging pages 8 and 9; and page 10, 2nd para.
Applicant concludes arguments stating the teachings of the prior art references and states a person having ordinary skill in the art (POSA) would not be motivated to combine the cited references as they fail individually or in combination of to render independent claim 1 obvious, see Remarks, page 10, paragraphs (paras.) 1 and 2.
Applicant’s arguments and points of view have been carefully reviewed and considered. They are not found persuasive.
Applicant’s independent claim 1 is silent as to the dosage unit, amount of both, poziotinib and T-DMI.
Kris teaches the quinazolinamine-based tyrosine kinase inhibitor was administered once-a-day, a single dose to patients with HER2-mutant tumors with mutations within exon 20, see page 1422, 2nd column (col.), 1st sentence. The Trials teaches women with advanced or metastatic HER2 positive breast cancer are treated with a daily dose of poziotinib in combination with T-DMI on day 1 of each 21-day cycle, see pages 2 and 3. Morimura teaches the suppression of the growth of HER2-positive cancer with T-DM1 with a single intravenous injection of 15mg/kg, which reads on a dose of about 10 mg/kg, see page 597, segment 2.6. Koga teaches “[p]oziotinib showed the most potent activity against HER2 exon 20 mutations”, see Abstract on page 72.
Moreover, it would not be outside the scope of the skilled artisan to substitute the tyrosine kinase inhibitor (TKI), dacomitinib of Kris with the TKI, poziotinib of the Trials and Koga. It is obvious to those skilled in the art to substitute one known equivalent for another. See In re Omeprazole Patent Litigation, 483 F.3d 1364, 1374 (Fed. Cir. 2007) (“[T]his court finds no . . . error in [the] conclusion that it would have been obvious to one skilled in the art to substitute one ARC [alkaline reactive compound] for another.”). It is art known at least nine TKIs do exhibit activity for HER2 mutations, see entire Koga document.
As noted in the last Action mailed August 13, 2025, “[t]he modification of the primary reference, in light of the secondary references is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213 USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious.”, see para. bridging pages 10 and 11.
And while Applicant’s arguments include terms, “surprisingly”, and “surprising”, Applicant has not presented any scientific evidence, nor declaration or affidavit to show that the results would have been unexpected to one of ordinary skill in the art and would dissuade the Office from the combination of references. Hence, the rejection is maintained and made for the reasons of record, the analysis and reasoning set forth herein.
Kris teaches treating “…adults with pathologically confirmed stage IIIB or IV lung adenocarcinomas” in addition to “HER2 mutations including exon 20 insertions, deletions, and point mutations in intra- or extracellular domains”, see Background, Patients…segment, and Results spanning pages 1421 and 1422; patients…segment spanning columns 1 and 2 on page 1422. “HER2 mutations included exon 20 insertions, deletions, and point mutations in intra- or extracellular domains.”, see page 1422, patients…segment in column 1; and sentence bridging pages 1424 and 1425. “The specific aberrations detected in the 26 patients with HER2 mutations are detailed in Table 1 [on page 1423]. Thirteen tumors harbored identical 12-bp exon 20 insertions [A775_G776insYVMA, alternative nomenclature p.Y772_A775dup(c.2313_2324dup)]. There were four 9-bp insertions and three 3-bp insertions.”, page 1422, column 2, last two sentences.
The adults were treated with a quinazolinamine-based tyrosine kinase inhibitor (TKI), dacomitinib (PF-00299804), see page 1422, Conclusions and entire 2nd column. The dacomitinib was administered once-a-day, see page 1422, 1st sentence in column 2.
Kris does not teach the additional administration of a HER antibody-drug conjugate that is trastuzumab emtansine (T-DM1) in a single dose of about 10 mg/kg and within a range from 2 mg/kg to about 3 mg/kg. Kris also does not teach the quinazolinamine-based TKI is poziotinib at a dosage range from about 2 mg/kg to about 3 mg/kg and a range from about 5mg to about 25mg. Kris also does not teach the subject is a non-human subject.
However, ClinicalTrials.gov ID NCT03429101 teaches treating women with advanced or metastatic HER2 positive breast cancer, see pages 2, 3 and 6. The women were treated with a quinazolinamine-based tyrosine kinase inhibitor (TKI), poziotinib in combination with trastuzumab emtansine (T-DM1), see title; and pages 2-5. The T-DM1 was administered once a day within a 21-day cycle, see page 3, Brief Summary; and page 4, Detailed Description. The standard dose of T-DM1 was 3.6 mg/kg IV, see page 3, last para.; and page 4, 1st and 5th paragraphs (paras.). The daily dose of poziotinib was 8 mg/day, see page 4, 1st paragraph of the Detailed Description.
Morimura teaches HER2-directed antibody-based drug, T-DM1 for in vivo treatment of HER2- positive small-cell lung cancer (SCLC) with a single intravenous injection of 15 mg/kg to a mouse, see Title; and section 2.6 on page 597.
Koga teaches poziotinib has “…the most potent activity against HER2 exon 20 mutations”, including point mutations, C805S, YVMA as well as mutations listed in claims 17, 19 and 21, see page Abstract on page 72; page 76, 2nd column, 1st full paragraph; Fig. B, C on page 77; page 78, column 1, 1st full and last paragraphs; and Supplementary Figures 1 and 2. Koga further teaches the implementation of additional TKIs, afatinib and neratinib, see page 72, Abstract; segment 2.3 Reagents on page 73; page 76, 2nd column, 1st full paragraph; and Table 1 on page 77.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the dacomitinib TKI of Kris with the poziotinib TKI of the Trials and Koga, see all three references. One of ordinary skill in the art would have been motivated by the teachings in the Trials and in particular, Koga that “[p]oziotinib showed the most potent activity against HER2 exon mutations.”, see the Koga abstract.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treatments of Kris, the Clinical trial, Morimura and Koga to arrive at the claimed invention because all the references report combining therapeutics for targeted HER2 treatment and utilizing human and non-human subjects, see all four references in their entireties. One of ordinary skill in the art would have been motivated by the teachings in the documents that targeted therapeutic combinatorial compositions are easily and successfully tested in mice and administered to HER2-mutant or amplified tumors and yield successful antitumor activity in particular to HER2 exon 20 mutations, see all references and in particular, Kris, Morimura and Koga.
It would been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treatments of Kris, the Clinical trial, Morimura and Koga to arrive at the effective amount, single dose of T-DMI of about 10mg/kg and range of poziotinib at 2.5 mg/kg and range from 5 mg to 25 mg, see all four references in their entireties. One of ordinary skill in the art would have been motivated by the teachings in the documents that a therapeutic component, T-DMI and poziotinib within the combinatorial treatment modality is easily and successfully administered with a reasonable expectation of success by teachings well known and noted herein that dosages of any pharmaceutical composition may be adjusted and optimized. One of ordinary skill in the art has been provided the general guidance and motivation to modify any of the two components of the successful combination of anti-cancer agents in light of the targeted treatment taught in all the documents and in particular the ClinicalTrials.
15. The rejection of claim(s) 1, 16, 17, 19, 21, 24-26, 30, 58-60 and new claims 61-68 under 35 U.S.C. 103 as being unpatentable over Kris et al. (Annals of Oncology 26:1421-1427, July 2015)/ IDS reference C13 submitted June 16, 2023), and further in view of Morimura et al. (Biochemical and Biophysical Research Communications 488: 596-602, available online 17 May 2017) and Koga et al. (Lung Cancer 126:72-79, published online October 17, 2018/ IDS reference C63 submitted September 6, 2024) is maintained and made. Claims 7, 56 and 57 have been cancelled.
Applicant incorporates the arguments and comments in previously cited pending 103 rejections into the Remarks for the instant rejection, see Remarks submitted February 13, 2026, paragraph (para.) bridging pages 11 and 12.
Initially, Applicant states as amended claim 1 “recites a method of treating a HER2 mutant cancer by administering a daily dose of poziotinib during a course of treatment of the subject and administering an effective amount of T-DM1 as a single dose to the subject during the course of treatment of the subject, wherein the HER2 mutant cancer comprises one or more mutations selected from the group consisting of [mutations]”, see Remarks submitted February 13, 2016, page 8, 2nd paragraph (para).; page 9, 2nd para.; and page 10, 1st para.
Applicant also states each reference is “…silent regarding any amount of poziotinib at any dosage, let alone administering [it]…in combination with a single dose T-DMI”, see page 10, 1st para. Furthermore, Applicant alleges none of the cited prior art teaches administering T-DMI as a single dose during the course of treatment and administering an effective amount of poziotinib in combination with a single dose of T-DMI, see page 10 of the Remarks, 1st full para.
Applicant asserts the alleged surprising teachings of their claimed invention, see Remarks, para. bridging pages 8 and 9; and page 10, 2nd para.
Applicant concludes arguments stating the teachings of the prior art references and states a person having ordinary skill in the art (POSA) would not be motivated to combine the cited references as they fail individually or in combination of to render independent claim 1 obvious, see Remarks, page 10, paragraphs (paras.) 1 and 2.
Applicant’s arguments and points of view have been carefully reviewed and considered. They are not found persuasive.
Applicant’s independent claim 1 is silent as to the dosage unit, amount of both, poziotinib and T-DMI.
Kris teaches the quinazolinamine-based tyrosine kinase inhibitor was administered once-a-day, a single dose to patients with HER2-mutant tumors with mutations within exon 20, see page 1422, 2nd column (col.), 1st sentence. The Trials teaches women with advanced or metastatic HER2 positive breast cancer are treated with a daily dose of poziotinib in combination with T-DMI on day 1 of each 21-day cycle, see pages 2 and 3. Morimura teaches the suppression of the growth of HER2-positive cancer with T-DM1 with a single intravenous injection of 15mg/kg, which reads on a dose of about 10 mg/kg, see page 597, segment 2.6. Koga teaches “[p]oziotinib showed the most potent activity against HER2 exon 20 mutations”, see Abstract on page 72.
Moreover, it would not be outside the scope of the skilled artisan to substitute the tyrosine kinase inhibitor (TKI), dacomitinib of Kris with the TKI, poziotinib of the Trials and Koga. It is obvious to those skilled in the art to substitute one known equivalent for another. See In re Omeprazole Patent Litigation, 483 F.3d 1364, 1374 (Fed. Cir. 2007) (“[T]his court finds no . . . error in [the] conclusion that it would have been obvious to one skilled in the art to substitute one ARC [alkaline reactive compound] for another.”). It is art known at least nine TKIs do exhibit activity for HER2 mutations, see entire Koga document.
As noted in the last Action mailed August 13, 2025, “[t]he modification of the primary reference, in light of the secondary references is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213 USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious.”, see para. bridging pages 10 and 11.
And while Applicant’s arguments include terms, “surprisingly”, and “surprising”, Applicant has not presented any scientific evidence, nor declaration or affidavit to show that the results would have been unexpected to one of ordinary skill in the art and would dissuade the Office from the combination of references.
Applicant argues the Examiner’s contention regarding the dose of poziotinib is incorrect. However, as noted above the claims do not cite any time construct (except for claim 7) and the administration of poziotinib at 8mg/day continues to read on the range presented in claim 1, as well as claim 7 and new claim 56, see page 4 of the Trials, 1st para. Moreover, "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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235(CCPA 1955). One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings well known in the art, that dosages of any pharmaceutical composition must be adjusted and optimized to arrive at the desired result. Accordingly, the rejection is maintained and made.
Kris teaches treating “…adults with pathologically confirmed stage IIIB or IV lung adenocarcinomas” in addition to “HER2 mutations including exon 20 insertions, deletions, and point mutations in intra- or extracellular domains”, see Background, Patients…segment, and Results spanning pages 1421 and 1422; patients…segment spanning columns 1 and 2 on page 1422. “HER2 mutations included exon 20 insertions, deletions, and point mutations in intra- or extracellular domains.”, see page 1422, patients…segment in column 1; and sentence bridging pages 1424 and 1425. “The specific aberrations detected in the 26 patients with HER2 mutations are detailed in Table 1 [on page 1423]. Thirteen tumors harbored identical 12-bp exon 20 insertions [A775_G776insYVMA, alternative nomenclature p.Y772_A775dup (c.2313_2324dup)]. There were four 9-bp insertions and three 3-bp insertions.”, page 1422, column 2, last two sentences.
The adults were treated with a quinazolinamine-based tyrosine kinase inhibitor (TKI), dacomitinib (PF-00299804), see page 1422, Conclusions and entire 2nd column. The dacomitinib was administered once-a-day, see page 1422, 1st sentence in column 2.
Kris does not teach the additional administration of a HER antibody-drug conjugate that is trastuzumab emtansine (T-DM1) in a single dose of about 10 mg/kg and within a range from 2 mg/kg to about 3 mg/kg. Kris also does not teach the quinazolinamine-based TKI is poziotinib at a dosage range from about 2 mg/kg to about 3 mg/kg and a range from about 5mg to about 25mg. Kris also does not teach the subject is a non-human subject.
However, Morimura teaches HER2-directed antibody-based drug, T-DM1 for in vivo treatment of HER2- positive small-cell lung cancer (SCLC) with a single intravenous injection of 15 mg/kg to a mouse, see Title; and section 2.6 on page 597.
And, Koga teaches poziotinib has “…the most potent activity against HER2 exon 20 mutations”, including point mutations, C805S, YVMA as well as mutations listed in claims 17, 19 and 21, see page Abstract on page 72; Fig. A, B, C on page 77; page 76, 2nd column, 1st full paragraph; page 78, column 1, 1st full and last paragraphs; and Supplementary Figures 1 and 2 Koga further teaches the implementation of additional TKIs, afatinib and neratinib, see page 72, Abstract; segment 2.3 Reagents on page 73; page 76, 2nd column, 1st full paragraph; and Table 1 on page 77.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the dacomitinib TKI of Kris with the poziotinib TKI of Koga, see Kris and Koga references. One of ordinary skill in the art would have been motivated by the teachings in Koga that “[p]oziotinib showed the most potent activity against HER2 exon mutations.”, see the Koga abstract.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treatments of Kris, Morimura and Koga to arrive at the claimed invention because all the references report combining therapeutics for targeted HER2-positive treatment, see all three references in their entireties. One of ordinary skill in the art would have been motivated by the teachings in Morimura to add T-DM1 to the combinatorial treatment of Kris and Kong because T-DM1 is able to induce cancer death and inhibited proliferation of tumor cells, as well as targeted therapeutic combinatorial compositions are easily and successfully administered to HER2-mutant or amplified tumors and yield successful antitumor activity in particular to HER2 exon 20 mutations, see all references in their entireties.
It would been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treatments of Kris, Morimura and Koga to arrive at the effective amount, single dose of T-DMI of about 10mg/kg and range of poziotinib at 2.5 mg/kg and range from 5 mg to 25 mg, see all three references in their entireties. One of ordinary skill in the art would have been motivated by the teachings in the documents that a therapeutic component, T-DMI and poziotinib within the combinatorial treatment modality is easily and successfully administered with a reasonable expectation of success by teachings well known and noted herein that dosages of any pharmaceutical composition may be adjusted and optimized. One of ordinary skill in the art has been provided the general guidance and motivation to modify any of the two components of the successful combination of anti-cancer agents in light of the targeted treatment taught in all the documents.
16. Claim(s) 1, 16, 17, 19, 21, 24-26, 30 and 58-68 are rejected under 35 U.S.C. 103 as being unpatentable over ClinicalTrials.gov ID NCT03429101 (first posted February 12, 2018/ IDS reference C1 submitted June 16, 2023) as evidenced by Bon et al. (Cancer Science 115(7): 2147-2158, May 7, 2024), and further in view of Morimura et al. (Biochemical and Biophysical Research Communications 488: 596-602, available online 17 May 2017) and Koga et al. (Lung Cancer 126:72-79, published online October 17, 2018/ IDS reference C63 submitted September 6, 2024). ClinicalTrials.gov ID NCT03429101 teaches treating women with advanced or metastatic HER2 positive breast cancer, see pages 2, 3 and 6. The women were treated with a quinazolinamine-based tyrosine kinase inhibitor (TKI), poziotinib in combination with trastuzumab emtansine (T-DM1), see title; and pages 2-5. As evidenced by Bon, exon 20 insertion mutation, Y772_A775dupYVMA occurs in HER2 breast cancers, see paragraph (para.) bridging pages 2149 and 2150; and Figure 2(B) on page 2150.
The T-DM1 was administered once a day within a 21-day cycle, see page 3, Brief Summary; and page 4, Detailed Description. The standard dose of T-DM1 was 3.6 mg/kg IV, which is within a range from 2mg/kg to about 3 mg/kg, see page 3, last para.; and page 4, 1st and 5th paragraphs (paras.). The daily dose of poziotinib was 8 mg/day, see page 4, 1st paragraph of the Detailed Description.
The Trials does not teach the subject is a non-human subject, the exon 20 point mutation is at residue C805S and the HER2 mutant cancer is lung cancer.
However, Morimura teaches HER2-directed antibody-based drug, T-DM1 for in vivo treatment of HER2- positive small-cell lung cancer (SCLC) with a single intravenous injection of 15 mg/kg to a mouse, see Title; and section 2.6 on page 597.
Koga teaches poziotinib has “…the most potent activity against HER2 exon 20 mutations”, including point mutations, C805S, YVMA as well as mutations listed in claims 17, 19 and 21, see page Abstract on page 72; page 76, 2nd column, 1st full paragraph; Fig. B, C on page 77; page 78, column 1, 1st full and last paragraphs; and Supplementary Figures 1 and 2. Koga further teaches the implementation of additional TKIs, afatinib and neratinib, see page 72, Abstract; segment 2.3 Reagents on page 73; page 76, 2nd column, 1st full paragraph; and Table 1 on page 77.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treatments of the Clinical Trial, Morimura and Koga to arrive at the claimed invention because all the references report combining therapeutics for targeted HER2 treatment and utilizing human and non-human subjects, see all references in their entireties. One of ordinary skill in the art would have been motivated by the teachings in the documents that targeted therapeutic combinatorial compositions are easily and successfully tested in mice and administered to HER2-mutant or amplified tumors and yield successful antitumor activity in particular to HER2 exon 20 mutations, see all references and in particular, Morimura and Koga.
It would been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the method treatments of the Clinical Trial, Morimura and Koga to arrive at the effective amount, single dose of T-DMI of about 10mg/kg and range of poziotinib at 2.5 mg/kg and range from 5 mg to 25 mg, see all references in their entireties. One of ordinary skill in the art would have been motivated by the teachings in the documents that a therapeutic component, T-DMI and poziotinib within the combinatorial treatment modality is easily and successfully administered with a reasonable expectation of success by teachings well known and noted herein that dosages of any pharmaceutical composition may be adjusted and optimized. One of ordinary skill in the art has been provided the general guidance and motivation to modify any of the two components of the successful combination of anti-cancer agents in light of the targeted treatment taught in all the documents and in particular the ClinicalTrials.
Conclusion
17. 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.
18. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached 8AM-8PM, Monday through Friday and occasionally Saturday evening.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
24 April 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643
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