DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant's amendment and remarks, filed 3/18/26, are acknowledged.
Claims 1, 3, 6-10 have been amended.
Claims 1, 3, 6-19 are pending and are under examination.
In view of Applicant’s claim amendments, only the following rejections remain.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 9 recites the limitation “the cell population enriched for immature human dendritic cells”. There is insufficient antecedent basis for this limitation in the claim.
Claim 10 recites the limitation “the cell population comprising the immature human dendritic cells” in part iii). There is insufficient antecedent basis for these limitations in the claim.
Applicant’s arguments filed 3/18/26 have been fully considered, but they are not persuasive.
Applicant argues that the amendment is remedial.
Regarding claim 9, “the cell population enriched for immature human dendritic cells” is still recited in the claim. It is noted that the previous office action had a typographical error indicating that the above limitation was in part iii), however, the limitation appears in part iv). Amendment to recite culturing the immature human dendritic cells would be remedial.
Regarding claim 10, the amend claim now recites “the cell population comprising the immature human dendritic cells”, which still lacks antecedent basis. Amendment to recite culturing “the immature human dendritic cells”, would be remedial.
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.
Claims 1, 3, 6-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2004/053072, in view of Jin et al., 2010, Muller-Berghaus, 2005, and Hellman, 2007 (all of record).
WO 2004/053072 teaches a method of producing an anti-tumor immune response comprising producing a partially, i.e. semi-mature dendritic cell, and administering said dendritic cell to an individual having a tumor (see page 3, in particular). WO 2004/053072 teaches that the dendritic cells can be partially matured with maturation agents including LPS, IFN-gamma, or a combination of BCG, and IFN-gamma, (see page 4, in particular). WO 2004/053072 teach inactivated BCG and the use of 105 to 107 cfu/ml and 100-1000 U/ml IFN-gamma ( see page 4, in particular). WO 2004/053072 teaches that the dendritic cell can be produced from the patient having the tumor (i.e. autologous), or from an HLA matched donor (see page 5, in particular). WO 2004/053072 teaches that the semi-mature dendritic cells are produced by obtaining non-activated monocyte dendritic cell precursor from peripheral blood and culturing in GM-CSF and IL-4 to produce immature dendritic cells, and then treating the immature dendritic cells with said maturation agents (see pages 9-10, in particular). WO 2004/053072 teaches monitoring the partial maturation of the dendritic cells, including for cytokine production, and teaches that typical cytokines produced by the partially mature dendritic cells include TNF-alpha, IL-6, and IL-12, which are not typically produced by immature dendritic cells (i.e. comparing to a threshold amount, see pages 11 in particular). WO 2004/053072 teaches that dendritic cells can be monitored by methods known in the art, and teaches the importance of ensuring that the administered dendritic cells are partially mature, and not immature (See page 11-12, in particular). Therefore, based on WO 2004/053072, it would be apparent that the dendritic cells selected should be capable of producing all of IL-6, IL12, and TNF-alpha, as a quality control measure to ensure that the partially mature, and not immature dendritic cells, i.e. “dendritic cells of high potency”, are being used for administration to enhance therapeutic efficacy of the method in WO 2004/053072. Similarly, it would be obvious that the patients to be treated with autologous dendritic cells would be those that have dendritic cells that can be produced in sufficient quality to produce the cytokines specifically taught to be important, i.e. TNF-alpha, IL-6, and IL-12.
The reference differs from the claimed invention in that it does not explicitly teach determining IL-8, nor determining IL-12p40 as the type of IL-12.
Muller-Berghaus teaches that IL-12 production can be measured by determining expression of IL-12p40. Muller-Berghaus teaches that IL-12p40 is not detectable in unstimulated, immature dendritic cells, but is produced rapidly after initiation of maturation from 5-24 hours after stimulation (see page 307, in particular). Muller-Berghaus teach that said IL-12p40 production is a feature of partially matured dendritic cells (See abstract and Figure 1, in particular). Muller-Berghaus teach the importance of quality-control in dendritic cell production for those properties that are affiliated with clinical efficacy (see page 306, in particular).
Hellmann teach determining cytokine levels between 0 and 8 hours after initiation of maturation and teach detecting an increase in IL-8, IL-6, and TNF-alpha (see page 328, in particular). In particular, Hellmann teach that IL-8 is an early marker of dendritic cell maturation that is rapidly produced after maturation initiation (See page 324 and 328, in particular).
Jin teaches that when developing dendritic cell therapies, it is important to compare products manufactured from different people for consistency and that assessing a dendritic cell manufacturing process for potency is crucial (see page 2, in particular). Jin et al. teach a method of testing for the quality of maturing, i.e. activated human dendritic cells for therapy (i.e. a method for determining immunotherapeutic potential) comprising contacting immature dendritic cells with maturation agents and determining a molecular signature at different times after maturation, such as 4, 8, or 24 hours after maturation induction. Jin et al. teach that certain genes are upregulated early in DC maturation, in particular, they teach that IL-8 is upregulated early after induction of maturation (see Table 3 and page 12, in particular). Jin also teaches that IL-12p40 is upregulated early after maturation (see page 11, in particular). Jin teach that when performing cellular therapies it is important to assess the manufacturing process to ensure for consistency and potency of the resulting cells and that cellular therapy laboratories test the function of dendritic cells, and that additionally biomarkers would also be useful (see page 2, in particular). Jin teaches that monitoring the kinetics of maturation is useful for assessing quality of dendritic cells for immunotherapy (see abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to determine cytokine levels and compare to a threshold, including assessing IL-8 and IL-12p40, as taught by Jin, Hellmann and Muller-Berghaus, as a quality control measure for the partially mature dendritic cells produced in the method of WO 2004/053072. The ordinary artisan would be motivated to include IL-8 in the evaluation in particular, since WO 2004/053072 teaches the importance of ensuring partially mature, rather than immature dendritic cells are selected, and Jin and Hellman both teach that IL-8 is specifically induced early in DC maturation, and would therefore be recognized as a biomarker that could be used to identify partially mature dendritic cells. Likewise, the ordinary artisan would be motivated to determine IL-12p40 as the type of IL-12 in the method of WO 2004/053072, since both Jin and Muller-Berghaus teach that it is induced early after maturation initiation and is a biomarker for partially matured dendritic cells. The ordinary artisan at the time the invention was made would have been motivated to perform the cytokine determinations and to compare with a threshold amount that correlates with clinical efficacy, to ensure consistency and potency of the dendritic cells as taught by the cited references. For example, Muller-Berghaus teach the importance of quality-control in dendritic cell production for those properties that are affiliated with clinical efficacy. WO 2004/053072 specifically teaches the criticality of ensuring partially mature, rather than immature dendritic cells are administered. Thus, one could use an amount produced by immature dendritic cells as the threshold, to ensure that the dendritic cells are of sufficient potency to induce a T cell response in the treated patient, i.e. a threshold correlated with improved clinical outcome. Both Jin and WO 2004/053072 teach that partial maturation induces cytokine production relative to immature dendritic cells, and the ordinary artisan could readily envision ensuring that the levels of IL-8, TNF, IL-6, and IL-12p40 were above said immature dendritic cell threshold to provide partially mature dendritic cells with immunotherapeutic potency, since WO 2004/053072 explicitly teaches that said partially mature dendritic cells are more “potent” than immature dendritic cells. Regarding the limitation of treating a patient with advanced cancer, it is noted that WO 2004/053072 teaches administration to a patient with a palpable tumor of a particular size (see page 16, in particular), and this would be recognized to be a type of “advanced” cancer, compared to those with non-palpable or just developing tumors, for example, and thus renders obvious the limitations of present claims.
Regarding claims 6-8, the claims, as amended, do not require comparing to a threshold amount comprising the ranges, but rather that the dendritic cells produce said amount. For example, the claims encompass comparing to a threshold amount of zero or to an amount produced by immature dendritic cells, wherein the selected dendritic cells produce cytokines in amounts of the claimed ranges. However, doing so would merely be a latent property that would flow naturally from following the suggestions of the prior art. For example, WO 2004/053072 teaches producing the dendritic cells by a process identical to that of the instant claims, i.e. a process comprising obtaining non-activated monocyte dendritic cell precursor from peripheral blood and culturing in GM-CSF and IL-4 to produce immature dendritic cells, using inactivated BCG in amounts of 105 to 107 cfu/ml and 100-1000 U/ml IFN-gamma. The prior art teaches evaluating cytokine production for 24 hours. Therefore, when following the teachings of the prior art to quality control check the 24 hour cytokine levels before treatment, at least some of the dendritic cells selected that produce cytokines above the immature dendritic cell threshold would naturally have levels within the recited ranges, since they are produced by a process identical to that of the instant claims. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).
Alternativity, the amounts could be achieved by routine optimization of the cell culture process and culture times of the prior art. As the references teaches the desirably of cytokine production for potency, as well as that the particular amounts produced can vary depending on the maturation process, timing, and assay used, it would be routine to optimize the level for each manufacturing process and maturation agent.
Applicant’s arguments filed 3/18/26 have been fully considered, but they are not persuasive. Applicant argues that the prior art compares to an immature dendritic cell threshold, while the present application recognizes that certain cytokines when produced above defined thresholds will produce an improved clinical outcome as measured by duration of survival.
The claims are not limited to improved duration of survival. For example, increased levels of T cell activation could be a clinical outcome. Nor do the claims exclude comparing to an immature dendritic cell threshold. The claims do not require any particular threshold amount. For example, the threshold amount could be zero, or the amount produced by immature dendritic cells, wherein selecting activated dendritic cells that produce higher levels than immature dendritic cells correlates with improved T cell responses, and hence improved treatment of cancer or survival, i.e. an improved clinical outcome. To the extent hat Applicant may be arguing unexpected results, it noted that that the specification in Figure 2B, for example, demonstrates improved survival in patient injected with activated dendritic cells producing greater than 330 ng/106/day IL-12p40 as compared to less than 330 ng/106/day. However, the present claims are not limited to comparison with a 330 ng threshold and selecting dendritic cells that produce above said threshold. For example, the threshold in claim 1 could be zero. Even claims 6 only requires that the dendritic produce 75-100 ng of IL-12 p40, which is below the amount shown in Fig. 2B as supposedly unexpectedly increased survival Thus the improved survival data is not commensurate in scope with the instant claims.
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.
Claims 1, 3, 6-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,124,768, in view of WO 2004/053072, Jin et al., 2010, Muller-Berghaus, 2005, and Hellman, 2007 (all of record).
The ‘768 patent claims a method of producing partially mature and activated human dendritic cells comprising producing partially mature and activated dendritic cells by isolating dendritic cell precursors, differentiating immature dendritic cells, and culturing the immature dendritic cells with heat inactivated BCG and IFN-gamma for about 16 hours without contact with an antigen, and isolating and washing the activated human dendritic cells. The ‘768 patent claims that the precursors are monocytic precursors obtained from peripheral blood, that the precursors are from an individual to be treated, or HLA-matched, that the dendritic cells are differentiated with GM-CSF and IL-4, that the amount of BCG is 105-107 cfu per milliliter of tissue culture media and the amount of IFN-gamma is 100 to about 1000 U per milliliter. Although the ‘768 patent does not specifically claim determining the amount of cytokines produced by the partially mature dendritic cells, it would be obvious to do so as a quality control measure based on the teachings of WO 2004/053072, Jin et al Muller-Berghaus, and Hellman for the same reasons set forth above.
Claims 1, 3, 6-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 17/477,949, in view of WO 2004/053072, Jin et al., 2010, Muller-Berghaus, 2005, and Hellman, 2007 (all of record).
The ‘949 application claims a method comprising producing partially mature and activated human dendritic cells for treating a tumor comprising producing partially mature and activated dendritic cells by isolating dendritic cell precursors, differentiating immature dendritic cells, and culturing the immature dendritic cells with heat inactivated BCG and IFN-gamma for about 10-19 hours without contact with an antigen, and isolating and washing the activated human dendritic cells. The ‘949 application claims that the precursors are monocytic precursors obtained from peripheral blood, that the precursors are from an individual to be treated, or HLA-matched, that the dendritic cells are differentiated with GM-CSF and IL-4, that the amount of BCG is 105-107 cfu per milliliter of tissue culture media and the amount of IFN-gamma is 100 to about 1000 U per milliliter. Although the ‘949 application does not specifically claim determining the amount of cytokines produced by the partially mature dendritic cells, it would be obvious to do so as a quality control measure based on the teachings of WO 2004/053072, Jin et al Muller-Berghaus, and Hellman for the same reasons set forth above.
This is a provisional nonstatutory double patenting rejection.
Applicant argues that the claims are not obvious for the same reasons set forth above.
The claims stand rejected for the reason set forth above.
The following are new grounds of rejection necessitated by Applicants’ amendment.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 7-8 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 7-8 depend from claim 6, and recite ranges that are outside of the range required in claim 6. For example, claim 6 requires particular amounts of IL-8, TNF, and IL-12, and claims 7-8 appear to broaden the range by reciting that the amounts can be “at least” 100 ng, which has no upper limit. For example, for TNF, the range in claim 6 is 30-70, and claim 7 recites “at least 30”, which is already the lower limit in claim 6. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
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