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
1. Applicant’s amendment and response filed 5/8/2026 is acknowledged and has been entered.
Claims 1-12, 14-16, 18, 20 and newly added claims 21 and 22 are presently being examined. Claims 1 and 12 are independent claims.
2. Claim interpretation: The specification (at [0044] and [00198]) discloses that “a” wild-type actinohivin is represented by SEQ ID NO: 1, and “an” actinohivin is a sugar-binding protein exhibiting anti-HIV virus activity, and was originally identified and isolated from the actinomycetes K97-0003 strain (citing IDS reference Chiba et al.). The specification discloses that “as used herein, the term “variant” refers to a polypeptide comprising an amino acid sequence that has at least about 70% sequence identity to a reference sequence, i.e., to a wild type actinohivin ([0046]). The specification further discloses that “subject” includes any human or nonhuman animal, including all vertebrates ([0036]) and that “subject in need thereof” refers to a mammalian subject diagnosed with or suspected of having a disease whom will be or has been administered a polypeptide according to a method of the invention. The “subject in need thereof” includes those subjects already with the undesired physiological change or disease as well as those subjects prone to have the physiological change or disease ([00123]). The specification discloses that “treating” encompasses preventing recurrence of the disorder or of symptoms thereof in subjects that were previously symptomatic for the disorder, reducing severity and/or duration of the disorder, inhibiting worsening of symptoms characteristic of the disorder ([00139]). The specification further discloses that in particular embodiments, the therapeutically effective amount is sufficient to significantly decrease tumor burden, improve survival or the likelihood of survival, or all three ([00145]). The specification discloses that “a therapeutically effective amount” is an amount effective to achieve a desired therapeutic response such as treatment, healing, inhibition or amelioration of physiological response or condition, but not a full therapeutic effect upon administration of one dose, but occurring after administration of a series of doses ([0040]). Instant claims 12 and 14-16 which recite a method of killing an epithelial ovarian cancer cell comprising contacting the epithelial ovarian cancer cell with a polypeptide comprising the recited actinohivin variant and an Ig Fc are being interpreted as encompassing contacting that is either in vitro or in vivo (by administration to a subject). Please note that SEQ ID NO: 16 is SEQ ID NO: 9 with a fused IgG1 Fc region.
3. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
4. Claims 1-12, 14-16, 18 and 20-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/8/26. Applicant has amended instant base claim 1 to recite “wherein the actinohivin variant comprises an amino acid sequence set forth in SEQ ID NO: 9”, indicating a subsequence of SEQ ID NO: 9 by the recitation of “an” instead of ‘the’. Although claim 17, that is now canceled, had recited SEQ ID NO: 9 with the article “an”, it also recited that “the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-15” which are fully defined amino acid sequences, thus limiting the claim to fully defined sequences, with the “optionally” limitation describing that a subsequence of SEQ ID NO: 9 is comprised within a fully defined amino acid sequence (for example, SEQ ID NO: 1 is not the same sequence as SEQ ID NO: 9 and neither does it comprise SEQ ID NO: 9, indicating the interpretation of that claim indicated a subsequence of SEQ ID NO: 9 is present in a fully defined sequence that is one of SEQ ID NO: 1-15). Claim 18 which also recited “and optionally, the polypeptide comprises an amino acid sequence set forth in SEQ ID NO: 16 (i.e., SEQ ID NO: 9 with an Fc region fused thereto) was included in the prior rejection of record for the same reason (i.e., a subsequence of SEQ ID NO: 16, and hence a subsequence of SEQ ID NO: 9, was encompassed therein). Applicant has also presently amended instant base claim 12 to recite “contacting…with a polypeptide comprising an actinohivin variant…, wherein the actinohivin variant comprises an amino acid sequence set forth in SEQ ID NO: 9”, thus encompassing a subsequence of SEQ ID NO: 9.
Applicant has broadly claimed:
a) a method of treating an epithelial ovarian cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a polypeptide comprising an actinohivin variant and a fragment crystallizable (Fc) region of immunoglobulin (Ig Fc), wherein the actinohivin variant comprises “an” amino acid sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 16 (claims 1-11, 18 and 20); and
b) a method of killing an epithelial ovarian cancer cell, the method comprises contacting the epithelial ovarian cancer cell with a polypeptide comprising an actinohivin variant and a fragment crystallizable (Fc) region of immunoglobulin (Ig Fc), wherein the actinohivin variant comprises “an” amino acid sequence (i.e., a subsequence of ) set forth in SEQ ID NO: 9 or SEQ ID NO: 16 (claims 12, 14-16, 21 and 22); and
c) either a) or b) wherein “the polypeptide is modified” (as is recited in instant dependent claims 20 and 22 that depend upon presently amended base claims 1 and 12, respectively), i.e., this encompasses modifications anywhere in SEQ ID NO: 9 or in a subsequence of SEQ ID NO: 9, and thus encompasses a variant of SEQ ID NO: 9. (The instant specification at [0032] gives non-limiting examples of modifications, but the specification does not provide a limiting example for “modified” or modify. For example, one modification is an analog (no limiting or other definition provided) of a peptide, indicating a variant of the peptide or polypeptide. The specification discloses modifications to the Fc portion of a (fully defined) actinhohivin variant polypeptide-Fc fusion (e.g., at [0064], [0067]), but the instant claims are not limited to modifications in only the Fc portion of the fusion polypeptide.)
Thus, the claims encompass a method of treating and epithelial ovarian cancer (EOC) in a subject in need thereof or killing an epithelial ovarian cancer (EOC) cell, wherein the administered agent is an actinohivin variant-Fc Ig polypeptide, wherein the actinohivin variant portion may only be a subsequence of SEQ ID NO: 9 or of SEQ ID NO: 16 plus or minus other additional non-recited N- and/or -C terminal sequence(s), i.e., “wherein the actinohivin variant comprises an amino acid sequence set forth in SEQ ID NO: 9” or “wherein the actinohivin variant comprises an amino acid sequence set forth in SEQ ID NO: 16”. The actinohivin variant must possess the functional properties of binding a sugar and possessing HIV-virus-inhibiting activity, as is enunciated below in detail.
The specification does not discloses a representative number of species of an actinohivin variant that comprises only a subsequence of SEQ ID NO: 9 or of SEQ ID NO: 16 (SEQ ID NO: 16 that does not comprise all of SEQ ID NO: 9) and does not provide a structure/function relationship for the subsequence(s) that must possess the said functional properties.
As is stated above in this office action in the claim interpretation section, the specification discloses that a wild-type actinohivin is represented by SEQ ID NO: 1, and an actinohivin is a sugar-binding protein exhibiting anti-HIV virus activity, and was originally identified and isolated from the actinomycetes K97-0003 strain (citing IDS reference Chiba et al.)([0044] and [00198]). The specification discloses that “as used herein, the term “variant” refers to a polypeptide comprising an amino acid sequence that has at least about 70% sequence identity to a reference sequence, i.e., a wild type actinohivin ([0046]). Thus, both “an” actinohivin and a “variant thereof” must possess the functional properties of being a sugar-binding protein that also has the functional property of anti-HIV virus activity.
The specification does not disclose a representative number of species of such actinohivin variant that consists of or comprises a subsequence of SEQ ID NO: 9 or of SEQ ID NO: 16 (i.e., of SEQ ID NO: 16 that does not comprise all of SEQ ID NO: 9) that is used in the claimed method of treatment or in the claimed method of killing an epithelial ovarian cancer cell, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli
Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.' " Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." See MPEP 2163 II.3.
The specification discloses that actinohivin variants are SEQ ID NO: 2-13, and SEQ ID NO: 16 is a fusion of SEQ ID NO: 9 variant [of SEQ ID NO: 1] and an Ig Fc sequence and is termed “”AvFc” or “Avaren Fc” ([00171]-[00172], [00177], [00213], [00293]).
Please note that SEQ ID NO: 9 is 113 amino acid residues in length, and SEQ ID NO: 1-8 and 10-13 are 113 or 114 amino acid residues in length and so accordingly do not provide written description support for a subsequence of SEQ ID NO: 9 that has the said requisite functional properties.
Evidentiary reference Hamorsky et al. (Mol. Ther. 2019, 27(11): 2038-2052, IDS reference, see entire reference) teaches that actinohivin (AH) is highly hydrophobic, prone to aggregate and is recalcitrant to efficient recombinant production. Hamorsky et al. teach that a soluble variant termed “Avaren” (an actinohivin variant) was obtained by structure-guided mutations of actinohivin [that is identical to instantly recited SEQ ID NO: 1] and subsequently fused to an IgFc region of human IgG1 subclass to create a “lectinbody” (paragraph spanning pages 2038-2039). Hamorsky et al. teach that this polypeptide possessed several advantages over the wildtype lectin, including higher HMG-binding avidity via dimerization, prolonged in vivo half-life and Fc-mediated antiviral/anti-tumor functions such as ADCC (paragraph spanning columns 1-2 on page 2039, Fig. 1 A at variant 8 (Avaren)). Hamorsky et al. teach that the overall structure in the variant appeared to be similar to that of actinohivin, although there appeared to be an increase in random
coils in Avaren’s structure (page 2039 at the last full paragraph at column 1).
Thus Hamorsky et al. evidence that experimentation must be employed to make a variant of SEQ ID NO: 1 that has anti-HIV activity and bind to the relevant sugar(s), i.e., one of the requisite functional properties [of lectin activity or sugar binding]. Except for the full length sequence of SEQ ID NO: 9, the specification nor the art, provide a structure/function relationship for an actinohivin variant that comprises a subsequence of SEQ ID NO: 9 or of SEQ ID NO: 16 (SEQ ID NO: 16 that does not comprise all of SEQ ID NO: 9). Nor do the specification and the art provide a representative number of species of such actinohivin variants, that possess the functional property of binding a sugar and in addition also possess the second requisite functional property of HIV-virus-inhibiting activity.
Also, with regard to the recitation of “wherein the polypeptide is modified” in instant dependent claims 20 and 22, the specification does not disclose a limiting definition for “modified”, but does disclose some examples at [0032]. Thus, it is clear that the term “modified” is much broader than the examples in the specification. As is stated above:
The instant specification at [0032] gives non-limiting examples of modifications, but the specification does not provide a limiting example for “modified” or modify. For example, one modification is an analog (no limiting or other definition provided) of a peptide, indicating a variant of the peptide or polypeptide. The specification discloses modifications to the Fc portion of a (fully defined) actinhohivin variant polypeptide-Fc fusion (e.g., at [0064], [0067]), but the instant claims are not limited to modifications in only the Fc portion of the fusion polypeptide.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the polypeptide ingredient that comprises an actinohivin variant that comprises “an” amino acid sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 16 that is recited in method of the instant claims, including one that is further “modified”. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such said polypeptide ingredients and hence was not in possession of the method that uses them at the time the instant application was filed.
Applicant may potentially obviate this rejection with regard to the points “a)” and “b)” above by amending the claims to recite “wherein the actinohivin variant comprises ‘the’ amino acid sequence set forth in SEQ ID NO: 9. With regard to point “c)” above, the issue of “wherein the polypeptide is modified”, Applicant may wish to recite specific modifications with regard to SEQ ID NO: 9 or to recite that the modifications occur in the Fc portion of the polypeptide with regard to SEQ ID NO: 16.
5. Applicant’s amendment filed 5/8/26 has overcome the prior rejection of record of claims 1-14, 16, 17, 19 and 20 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement.
Applicant has amended the claims to recite that the polypeptide comprising the actinohivin variant also comprises an Ig Fc portion.
6. Applicant’s amendment filed 5/8/26 has overcome the prior rejection of record of claims 1, 6-9, 12 and 15-20 under 35 U.S.C. 102(a)(i) as being anticipated by WO 2018148541 A1 (pub date 8/16/18, IDS reference).
Applicant has amended the claims to recite that the ovarian cancer is epithelial ovarian cancer, a limitation the art reference does not teach.
7. Upon further consideration and the present claim amendments the prior rejection of record of claims 1-20 under 35 U.S.C. 103 as being unpatentable over WO 2018148541 A1 (IDS reference) in view of US 2015/0125517 A1 (IDS reference) a is hereby withdrawn.
8. 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.
9. 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.
10. Claims 1, 3-12, 14-16, 18 and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018148541 A1 (IDS reference) in view of US 2015/0125517 A1 (IDS reference), and Chen et al. (Tumor Biol. 7/2017, pages 1-12, of record).
Changes to this rejection are necessitated by Applicant’s amendment filed 5/8/26.
WO 2018148541 A1 teaches that AvFc (i.e., SEQ ID NO: 16 of the art reference that is identical to instantly recited SEQ ID NO: 16 and is an actinohivin variant comprising a sequence identical to instantly recited SEQ ID NO: 9 fused to a human IgG1 Fc), may be used to treat ovarian cancer in a subject, including a human, and is administered in a therapeutically effective amount, including by an IV route. WO 2018148541 A1 teaches that AvFc may be used to treat cancer cells having high-mannose-type glycans on a cell membrane (e.g., abstract, [0012], [0024], [0029]-[0044], [0063], [0064], [0093],[0095], [0096], [0098], [00136],[00137], [00101], [00139]).
WO 2018148541 A1 teaches that AvFc and actinohivin (AH) both exhibited high specificity to oligomannose glycans containing terminal alpha-1, 2-linked mannose (i.e., a sugar) (e.g., [00137]) and have affinity to HIV gp120 proteins (e.g., [00138]). WO 2018148541 A1 teaches that AvFc can elicit Fc-mediated antiviral activity in addition to HIV virion neutralization (e.g., [00138]). (As enunciated above in the claim interpretation section of this office action, the instant specification discloses that an actinohivin is a sugar-binding protein exhibiting anti-HIV virus activity, e.g., at [0044] and [00198])). WO 2018148541 A1 teaches that AvFc was capable of inducing ADCC with less than or equal to 1 ug/mL effective concentrations against multiple cancer cells in vitro, without cytotoxicity or mitogenicity to/in human PBMCs (e.g., [00101]). WO 2018148541 A1 teaches that “the AvFc lectibody holds unique immunotherapeutic capabilities against a broad range of carcinomas and a good safety profile upon IV administration ([00101]), as well as potent ADCC comparable to a therapeutic antibody ([00139]), with binding in the nanomolar range ([00139]). WO 2018148541 A1 teaches that the terms treatment or treating include, but are not limited to, prophylaxis, reducing the likelihood of occurrence of a condition or development thereof, inhibiting the progression of a condition including a cancer, arresting development of a condition, reducing severity of a condition, ameliorating or relieving symptoms associated with a condition, and causing a regression of the condition, or ameliorating one or more of the symptoms thereof ([0090]). WO 2018148541 A1 teaches that a therapeutically effective amount refers to the amount of a composition comprising an actinohivin variant polypeptide sufficient to produce a measurable biological response ([0096]). WO 2018148541 A1 teaches that anti-cancer activity includes reduction in tumor burden (e.g., [000141], Fig. 14A,B). WO 2018148541 A1 teaches that the actinohivin variant polypeptide in some embodiments is fused or linked to an antibody fragment that may be a Fab ([0063]). WO 2018148541 A1 teaches that other drugs may be included in the composition with the polypeptide (i.e., a second therapeutic agent, e.g., [0096]). See entire reference, including claims 1-7.
WO 2018148541 A1 does not teach wherein the ovarian cancer is epithelial ovarian cancer, nor wherein the subject has undergone primary therapy and has achieved no residual disease status (claim 3), nor wherein the subject has relapsed (recurrent) or has refractory ovarian cancer (claim 4), nor wherein the cancer is chemo-resistant (claims 5 and 14).
US 2015/0125517 A1 discloses a method to treat ovarian cancer wherein the ovarian cancer is epithelial ovarian cancer ([0011]). US 2015/0125517 A1 further discloses treating epithelial ovarian cancer wherein the subject has undergone primary therapy and has achieved no residual disease status and to prevent recurrence to extend progression free survival ([0051]). US 2015/0125517 A1 discloses wherein the subject has relapsed or has refractory ovarian cancer such as platinum-refractory or platinum-resistant ovarian cancer ([0028], [0004]). US 2015/0125517 A1 discloses that ovarian cancer and cancer of the ovary are synonymous, in representative embodiments, refer to “epithelial ovarian cancer” and “epithelial cancer of the ovary” including without limitation, the various histological subtypes as well as localized and/or metastatic, and also encompasses recurrent and/or platinum-resistant or platinum-refractory ovarian cancer (i.e., chemo-refractory or chemo-resistant epithelial ovarian cancer) (e.g., [0028], [0058]). US 2015/0125517 A1 discloses that treatment may be practiced to prevent recurrence and/or metastasis ([0051]). See entire reference.
Chen et al. teach that N-mannnose glycans (i.e., oligomannan glycans such as those taught by the primary art reference WO 2018148541 A1 to be bound by actinohivin) are present on epithelial ovarian cancer cells (see entire reference, especially abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have treated an epithelial ovarian cancer patient, including
wherein the patient has undergone primary therapy and has achieved no residual disease status, or wherein the subject has relapsed or has refractory epithelial ovarian cancer, including platinum-refractory epithelial ovarian cancer. It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have administered AvFc in combination with a second therapeutic agent as is taught by the primary art reference.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to treat patients who have epithelial ovarian cancer, including patients who have relapsed, have refractory epithelial ovarian cancer or chemo-resistant epithelial ovarian cancer, particularly in light of the teaching of the primary art reference that ovarian cancer can be treated by AvFc and that it binds with high specificity to oligomannose glycans containing terminal alpha-1, 2-linked mannose and the teaching of Chen et al. that such oligomannan glycans are present on epithelial ovarian cancer cells.
Claims 12-16 are also included in this rejection because the method of killing an ovarian cancer cell comprising contacting the ovarian cancer cell with a polypeptide comprising an actinohivin or a variant thereof encompasses contacting that is either of in vitro or in vivo contacting (the latter by administration to a subject). Claims 10 and 11 are included in this rejection because it would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have treated an epithelial ovarian cancer patient as either an outpatient or an inpatient in order to accommodate the state of the patient.
Applicant’s arguments in the amendment and response filed 5/8/26 on pages 8-13 have been fully considered but are not persuasive as regards the claims included in the instant rejection.
Applicant argues that the application as filed demonstrates that AvFc binds to human and murine ovarian cancer cell lines at a high level with saturation occurring at 13 nm, is a potent inducer of ADCC with EC50 values in the low nM range, and it significantly improves survival in a mouse EOC model.
However, the primary art reference WO 2018148541 A1 teaches commensurate properties. The primary art reference teaches that AvFc binds to and therefore can be used to treat cancer cells having high-mannose-type glycans on a cell membrane, with binding in the nanomolar range. The primary art reference further teaches that AvFc was capable of inducing ADCC with less than or equal to 1 ug/mL effective concentrations against multiple cancer cells in vitro, without cytotoxicity or mitogenicity to/in human PBMCs. WO 2018148541 A1 teaches that the AvFc lectibody holds unique immunotherapeutic capabilities against a broad range of carcinomas and has a good safety profile upon IV administration ([00101]) as well as potent ADCC comparable to an anti-tumor therapeutic antibody ([00139]). (Please note that claim 2 that recites “is sufficient to improve survival of the subject” is not included in this rejection, as it would not have been predictable that survival would improve even if the condition was treated. Applicant has demonstrated that AvFc significantly improves survival in a mouse EOC model. Also please note that the limitation “survival” is recited in the alternative to “decrease tumor burden” in dependent claim 6 which is included in this rejection.)
Applicant further argues that there is no motivation to combine ‘541 and ‘517 because ‘541 exemplifies treatment of lung metastatic nodules of melanoma cells, and ‘541 does not disclose binding of AvFc to EOCs (epithelial ovarian cancer cells) or use of AvFc to treat or kill EOC cells. Applicant argues that ‘517 teaches a different treatment for EOC than use of AvFc. Applicant argues that the Office Action does not provide evidentiary basis or articulate a motivation to combine references ‘541 with ‘517. Applicant also argues impermissible hindsight.
However, first of all Applicant is ignoring the teaching of Chen et al. and the prior rejection of record did provide evidentiary basis and motivation to combine the references. The ‘541 reference does teach treating ovarian cancer and other cancer cells having high-mannose-type glycans on their membranes using AvFc, as well as the superior binding and ADCC against carcinomas, though it does not exemplify it. Chen et al. teach that epithelial ovarian cancer cells comprise these glycans on their cell membranes, while US 2015/0125517 A1 discloses epithelial ovarian cancer is a type of ovarian cancer (EOC) as well as recurrent, drug refractory of chemo-resistant EOC (albeit treating it with a different agent), thereby providing motivation to combine the references. Thus, one of ordinary skill in the art would have been motivated to combine the references and with a reasonable expectation of success in doing so, in order to kill EOCs or to treat an EOC in a subject. This addresses Applicant’s argument regarding the In Hulu PTAB case, i.e., there is an articulated reason to combine the references. The Johns Manville case cited by Applicant is not a precedential case.
Applicant is also arguing the references separately. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to Applicant's argument that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, the primary art reference teaches treatment of cancer cells having high-mannose type glycans, Chen et al. teach epithelial ovarian carcinoma cells have these types of glycans on their surface, and ‘517 teaches types of EOC, thereby providing teachings and motivation to combine the references that does not constitute hindsight reasoning, and providing a reasonable expectation of success in killing EOC tumor cells. The instant specification discloses that “treating” includes reducing the tumor size (e.g., [0013], [0095], [0096]), while killing tumor cells is expected to reduce tumor size. Binding to an EOC and killing it with ADCC activity reduces tumor size by killing EOCs. Administration of the AvFc would also be expected to inhibit the severity of the disorder by killing tumor cells.
Applicant’s further arguments alleging no reasonable expectation of success in improvement of overall survival or progression-free survival is off-point as Applicant is arguing a non-recited limitation (with the exception of claim 6 that also recites “sufficient to decrease tumor burden” in the alternative to improving survival, or claim 2 that is not included in this rejection). This is also relevant to Applicant’s argument that Chen et al. do not teach or suggest that polypeptides comprising an AvFc can improve survival of subjects having EOC. Applicant is also arguing Chen et al. and ‘541 separately. With regard to the instant rejection, the primary art reference teaches that the presence of oligomannan glycans on an ovarian cancer cell is a target for treatment with AvFc, with AvFc exhibiting high specificity and potent ADCC for killing such cells, while Chen et al. teach that epithelial ovarian cancer cells have these oligomannan glycans on their surface. It is therefore not speculative that cancer cells having these targets would be killed.
11. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed.Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP §717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See
MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
12. Applicant’s amendment filed 5/8/26 has overcome the prior rejection of record of claims 1, 6-9, 12 and 15-20 as provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9, 10, 12 and 17 of copending Application No. 18/261,950 in view of WO 2018148541 A1 (IDS reference).
Applicant has amended the instant claims to recite that the ovarian cancer is an epithelial ovarian cancer, a limitation that the claims of ‘950 do not recite, nor does the reference WO 2018148541 A1 teach. Applicant has also presently canceled claim 17 and 19.
13. Claims 1, 4, 6-12, 15, 16, 18 and 20-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9, 10, 12 and 15-22 of copending Application No. 18/261,950 in view of WO 2018148541 A1 (IDS reference) and Chen et al. (Tumor Biol. 7/2017, pages 1-12), as evidenced by admissions in the specification of 18/261,950 at [00367] and [00274] and by admissions in the instant specification at [00206] and [00213].
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/8/26 (and by the amendment filed 4/16/26 in application 18/261,950).
Claims 9 and 15-22 of 18/261,950 are drawn to a method of treating a cancer in a subject in need thereof, comprising administering or providing for administration a therapeutically effective amount of a polypeptide that specifically binds the high-mannose-type glycan epitope to the subject if abnormal accumulation in a biological sample from the subject is determined to be present. The polypeptide in claim 19 of ‘950 comprises an amino acid sequence set forth in SEQ ID NO: 9 (identical to instantly recited SEQ ID NO: 9). The polypeptide recited in claim 22 of ‘950 comprises an amino acid sequence set forth in SEQ ID NO: 16 (identical to instantly recited SEQ ID NO: 16).
The admissions in the specification of 18/261,950 at [00367] and [00274] are that SEQ ID NO: 9 is the amino acid sequence of Avaren also designated as variant 8 and that SEQ ID NO: 16 is the amino acid sequence that comprises SEQ ID NO: 9 fused via a linker polypeptide to an Fc, and referred to as “AvFc”. (Please note that the instant specification at [00206] discloses that instantly recited SEQ ID NO: 9 is Avaren or variant 8, while the instant specification at [00213] discloses that instantly recited SEQ ID NO: 16 comprises SEQ ID NO: 9 fused via a linker polypeptide to an Fc and is referred to as “AvFc”.)
Claim 10 and 12 of 18/261,950 are drawn to a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a polypeptide that specifically binds a high-mannose-type glycan epitope, wherein the cancer is characterized by an abnormal cell-surface accumulation of high-mannose glycans.
The claims of 18/261,950 do not recite wherein the ovarian cancer is epithelial ovarian cancer), nor that the polypeptide is administered in an inpatient or outpatient clinical setting (as is recited in instant claims 11 and 10, respectively), nor that the polypeptide is administered in combination with a second therapeutic agent.
WO 2018148541 A1 teaches that AvFc (i.e., SEQ ID NO: 16 of the art reference that is identical to instantly recited SEQ ID NO: 16 and is an actinohivin variant comprising a sequence identical to instantly recited SEQ ID NO:9 fused to a human IgG1 Fc) or other actinohivin variant polypeptides, including SEQ ID NO: 2-15 that are identical to their instantly recited counterpart sequences or Fc fusions thereof, may be used to treat ovarian cancer in a subject, including a human, and administered in a therapeutically effective amount, including by an i.v. route (e.g., abstract, [0029]-[0044], [0063], [0064], [0093],[0095], [0096], [0098], [00136],[00137]). WO 2018148541 A1 teaches that AvFc
and actinohivin (AH) both exhibited high specificity to oligomannose glycans containing terminal alpha-1, 2-linked mannose (i.e., a sugar) (e.g., [00137]) and have affinity to HIV gp120 proteins (e.g., [00138]). WO 2018148541 A1 teaches that AvFc can elicit Fc-mediated antiviral activity in addition to virion neutralization (e.g., [00138]). (As enunciated above in the claim interpretation section of this office action, the instant specification discloses that an actinohivin is a sugar-binding protein exhibiting anti-HIV virus activity, e.g., at [0044] and [00198])). WO 2018148541 A1 teaches that the terms treatment or treating include, but are not limited to, prophylaxis, reducing the likelihood of occurrence of a condition or development thereof, inhibiting the progression of a condition, arresting development of a condition, reducing severity of a condition, ameliorating or relieving symptoms associated with a condition, and causing a regression of the condition or one or more of the symptoms thereof ([0090]). WO 2018148541 A1 teaches that a therapeutically effective amount refers to the amount of a composition comprising an actinohivin variant polypeptide sufficient to produce a measurable biological response ([0096]). WO 2018148541 A1 teaches that anti-cancer activity includes reduction in tumor burden (e.g., [000141], Fig. 14A,B). WO 2018148541 A1 teaches that the actinohivin variant polypeptide in some embodiments is fused or linked to an antibody fragment that may be a Fab ([0063]). WO 2018148541 A1 teaches that other drugs may be included in the composition with the polypeptide (i.e., a second therapeutic agent, e.g., [0096]). See entire reference.
Chen et al. teach that N-mannnose glycans (i.e., oligomannan glycans such as taught by the primary art reference to be bound by actinohivin) are present on epithelial ovarian cancer cells (see entire reference, especially abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have treated ovarian cancer as taught by ‘541 including epithelial ovarian cancer taught by Chen et al. as the cancer being treated in the method recited in the claims of 18/261,950. It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have included a second therapeutic agent as is taught by ‘541.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to reduce the tumor burden in the subject as is taught by WO 201848541 A1. This is so particularly in light of the teaching of WO 201848541 A1 that ovarian cancer can be treated with the same polypeptides that are recited in the claims of 18/261,960 and that these polypeptides bind with high specificity and high affinity to oligomannose glycans containing terminal alpha-1, 2-linked mannose on tumor cells, along with the teaching of Chen et al. that these oligomannose glycans are present on epithelial ovarian cancer cells.
Claims 10 and 11 are included in this rejection because it would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have treated an ovarian cancer patient as either an outpatient or an inpatient in order to accommodate the state of the patient.
Instant claim 4 is included in this rejection because claims 15 and 16 of ‘950 recite that the cancer is resistant to treatment with an antibody the binds a growth factor receptor, including wherein the growth factor receptor is EGFR, i.e., the cancer is refractory to primary treatment with an anti-EGFR antibody agent. Evidentiary reference Siwak et al. (J. Oncol. 2009, volume 2010, Article ID 568938, pages 1-20) teaches that epithelial ovarian cancers express aberrant EGFR expression and activation, and are minimally responsive to anti-EGFR agents (see entire reference, especially abstract and introduction).
Instant claims 20 and 22 are included in this rejection because ‘541 teaches modifying the AvFc to reduce immunogenicity (e.g., [00142]), i.e., it is modified.
A comparison of SEQ ID NO: 16 in the instant application and SEQ ID NO: 16 in ‘950 indicates 100% amino acid sequence identity (and hence 100% sequence identity of SEQ ID NO: 9 which is comprised therein):
Program: needle
# Rundate: Tue 21 Jul 2026 21:20:28
# Commandline: needle
# -auto
# -stdout
# -asequence emboss_needle-I20260721-212023-0677-71932013-p2m.asequence
# -bsequence emboss_needle-I20260721-212023-0677-71932013-p2m.bsequence
# -datafile EBLOSUM62
# -gapopen 10.0
# -gapextend 0.5
# -endopen 10.0
# -endextend 0.5
# -aformat3 pair
# -sprotein1
# -sprotein2
# Align_format: pair
# Report_file: stdout
########################################
#=======================================
#
# Aligned_sequences: 2
# 1: EMBOSS_001
# 2: EMBOSS_001
# Matrix: EBLOSUM62
# Gap_penalty: 10.0
# Extend_penalty: 0.5
#
# Length: 350
# Identity: 350/350 (100.0%)
# Similarity: 350/350 (100.0%)
# Gaps: 0/350 ( 0.0%)
# Score: 1943.0
#
#
#=======================================
EMBOSS_001 1 ASGTIRNAETGRCLDSNYNGNVYTLPCNGGNYQRWTGPGDGTVRNAETGR 50
EMBOSS_001 1 ASGTIRNAETGRCLDSNYNGNVYTLPCNGGNYQRWTGPGDGTVRNAETGR 50
EMBOSS_001 51 CLDSNYDGAVYTLPCNGGSYQKWTGPGDGTIQNAETGRCLDSNYNGNVYT 100
EMBOSS_001 51 CLDSNYDGAVYTLPCNGGSYQKWTGPGDGTIQNAETGRCLDSNYNGNVYT 100
EMBOSS_001 101 LPCNGGNYQKWTGGGGSVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP 150
EMBOSS_001 101 LPCNGGNYQKWTGGGGSVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP 150
EMBOSS_001 151 KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 200
EMBOSS_001 151 KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 200
EMBOSS_001 201 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 250
EMBOSS_001 201 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ 250
EMBOSS_001 251 VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV 300
EMBOSS_001 251 VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV 300
EMBOSS_001 301 LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 350
EMBOSS_001 301 LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 350
Also please note that claim 18 of ‘950 recites “wherein the polypeptide comprises an amino acid sequence that is at least about 90% identical to at least one sequence set forth in SEQ ID NOs: 1-13.” For example, a comparison of the amino acid sequences of SEQ ID NO: 9 and SEQ ID NO: 3 reveals 95% amino acid sequence identity.
Applicant has stated in the amendment and response filed 5/8/25 on page 13 that Applicant disagrees with the provisional rejections previously of record for the reasons detailed in the response to the 103 rejection. To the extent that said arguments pertain to the instant rejection, Examiner’s rebuttal thereto also applies hereto.
14. Claims 3 and 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims9, 10, 12 and 15-22 of copending Application No. 18/261,950 in view of WO 2018148541 A1 (IDS reference) and Chen et al. (Tumor Biol. 7/2017, pages 1-12), as applied to claims 1, 4, 6-12, 15, 16, 18 and 20-22 above, as evidenced by admissions in the specification of 18/261,950 at [00367] and [00274] and by admissions in the instant specification at [00206] and [00213], and further in view of US 2015/0125517 A1 (IDS reference).
This is a new ground of rejection necessitated by Applicant’s amendment filed 5/8/26 (and by the amendment filed 4/16/26 in application 18/261,950).
The claims of 18/261,950 in view of WO 2018148541 A1 (IDS reference) and Chen et al. (Tumor Biol. 7/2017, pages 1-12) do not recite/teach that the subject has undergone primary therapy and has achieved no residual disease status (as is recited in instant claim 3), nor wherein the cancer is chemo-resistant (as is recited in instant claims 5 and 14).
US 2015/0125517 A1 discloses a method to treat ovarian cancer wherein the ovarian cancer is epithelial ovarian cancer ([0011]). US 2015/0125517 A1 further discloses treating ovarian cancer wherein the subject has undergone primary therapy and has achieved no residual disease status and to prevent recurrence to extend progression free survival ([0051]). US 2015/0125517 A1 discloses wherein the subject has relapsed or has refractory ovarian cancer such as platinum-refractory or platinum-resistant ovarian cancer ([0028], [0004]).
It would have been prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention to have treated an epithelial ovarian cancer patient, wherein the patient has undergone primary therapy and has achieved no residual disease status, wherein the subject has relapsed or has platinum-refractory ovarian cancer, all of which are disclosed by the US 2015/0125517 A1 art reference.
One of ordinary skill in the art would have been motivated to do this, and with a reasonable expectation of success in doing so, in order to treat patients who have particular subtypes of epithelial ovarian cancer.
Applicant has stated in the amendment and response filed 5/8/25 on page 13 that Applicant disagrees with the provisional rejections previously of record for the reasons detailed in the response to the 103 rejection. To the extent that said arguments pertain to the instant rejection, Examiner’s rebuttal thereto also applies hereto.
15. No claim is allowed.
16. 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.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights