DETAILED ACTION
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 .
Claim Status
Claim 17,24, and 27 are amended.
Claim 28 is new.
Claims 17,19-21,and 23-28 are under examination.
Withdrawn rejections
Rejections under 35 USC § 102
The rejection of claims 17,19-21, and 23-27 under 35 U.S.C. 102(a) (1) as being anticipated by Maxhimer et al ( Radiation Therapy, 2009). As evidenced by Dou et al ( Cellular and molecular immunology,2007), and Eramo et al (Cell death and differentiation, 2008) is withdrawn in view of claim amendments and the affidavit under 37 CFR 1.132 filed 10/08/20205. Applicants amended claim 17 to recite “directly contacting the CSC with an antisense morpholino oligonucleotide”. The method of Maxhimer et al involves indirectly engaging CSCs with an antisense morpholino oligonucleotide complementary to CD47. Therefore, the rejection is withdrawn.
Rejections under 35 USC § 103
The rejections of claims 17, 19-21, and 23-27 under 35 U.S.C. 103 as being unpatentable over Lee et al ( Hepatology, 2014) in view of Maxhimer et al ( Radiation Therapy, 2009) as evidenced by Dou et al ( Cellular and molecular immunology,2007), and Eramo et al (Cell death and differentiation, 2008) is withdrawn in view of claims amendment.
New Grounds of Rejections
Applicant’s arguments have been carefully considered but are not found persuasive. The new grounds of rejection below address the newly added claim as well as applicants remarks with respect to claim limitations recited in prior arts.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 17,19-21, and 23-28 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al ( Hepatology, 2014) in view of Maxhimer et al ( Radiation Therapy, 2009), and Baccelli et al as evidenced by Dou et al ( Cellular and molecular immunology,2007), and Eramo et al (Cell death and differentiation, 2008).
Regarding claim 17,19, and 28, Lee et al teach that CD47 is preferentially expressed in liver cancer stem cells (CSCs). Lee et al demonstrate that liver CSCs are capable of tumor initiation and self-renewal in the presence of chemotherapeutic agents, and they can also be enriched using CD47. ( See Fig.1A-1B, and supplementary Fig.1B-D). Lee et al further demonstrate that hepatocellular carcinoma cell lines (HCC) and patient samples are enriched with liver CSCs that express CD47. (See Fig.2A-C, and supporting table 1A-D). Furthermore, Lee et al show that using a morpholino approach to suppress the CD47 expression in cell lines and patient-derived xenograft models inhibits hepatocellular carcinoma growth and sensitizes cells to the effect of chemotherapy by blocking CTSS/PAR2 signaling.( Fig.6A-C). In addition, Lee et al disclose that suppressing CD47 expression in HCC cells using an shRNA approach reduces stem cell characteristics and the in vivo tumor initiating ability, as evidenced by the significant reduction in the number and size of the Hepatospheres, as well as the reduced tumor-forming incidence in a xenograft mouse model (See Fig.3B-C). It should be noted that, while the method of Lee et al does not involve sorting HCC cell lines and the patient samples for cancer stem cells prior to the administration of the morpholino, Lee et al’s method still involves directly contacting CSCs within HCC cells and patient samples with the morpholino, as both have been shown to be enriched with CSCs. This is demonstrated by the teachings, which show that the expression of CD47 in the HCC cells ( i.e.Huh-7 and MHCC-97L) highly overlaps with that of the cancer stem cell markers such as CD133,CD24, and EpCAM, implying that these cell lines contain high population of liver cancer stem cells. Taken together, the teachings of Lee et al clearly demonstrate to an ordinary skill in the art the value for directly contacting cancer stem cells that express CD47 with either an antisense morpholino oligonucleotide or an shRNA approach to suppress CD47 expression. Lee et al also teach that the loss of stemness and hence the antitumor activity of CD47 in the liver CSCs is mediated through blockade of CTSS/PAR2 signaling, which is independent of SIRPα. (See Fig.4,Fig.5 and Fig.6C ). However, applicants are again reminded that such results is an inherent property as it recites functional outcomes. This functional outcome is considered inherent, because it flows from performing the active steps of the method (i.e. contacting CD47-expressing CSCs with antisense morpholino complementary to CD47 ) which is taught by Lee et al, and there is nothing in applicants' disclosure that indicates that this functional result is necessarily limited to a specific step that achieves the recited function. For example, upon reviewing the specification, while the examples involve sorting the MDA231 breast cancer cell lines for CD44 hi/CD24 low cells (i.e. CSCs) prior to the administration of the anti-CD47 monoclonal antibody, wherein the anti-CD47 antibody is functionally equivalent to the morpholino, however the recited method of instant disclosure consists of a single active step comprising of directly engaging CSCs with anti-CD47 antibody/morpholino, which is also taught by Lee et al. Therefore, the recitation that “ inducing SIRPa-independent differentiation of the CSC” is considered a functional outcome that results from performing the active step of the method which does not lend patentability to an otherwise unpatentable invention. Applicant is reminded that the recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.
As per the MPEP “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)
Lee et al do not teach CSC comprising a breast, a lung, a prostate, a colon, or a melanoma stem cell.
Maxhimer et al show that contacting melanoma or squamous lung carcinoma tumors with antisense morpholino complementary to CD47 sensitizes tumor cells to radiotherapy. Specifically, Maxhimer et al teach that the use of morpholino, which is complementary to the CD47, in a xenograft animal model bearing the murine melanoma B16F10 or the murine squamous cell lung carcinoma (SCCVII) tumors. Maxhimer et al demonstrate that treating tumor-bearing limbs with the CD47 morpholino followed by irradiation dramatically delayed tumor regrowth by 89% compared to irradiation alone. (Fig. 6A-C). Maxhimer et al do not teach the presence of CSCs in the B16F10 or in the SCCVII cell lines, however the presence of CSCs is a known property of these cell lines, as evidenced by Dou and Eramo. (See Dou et al et al 2007, Abstract) and (Eramo et al 2008, Abstract, Fig.2 and Fig.5 ). Therefore, the method of Maxhimer et al involves indirectly contacting melanoma cancer stem cells and lung cancer stem cells with an antisense morpholino complementary to CD47.
Furthermore, Baccelli et al demonstrate that circulating tumor cells (CTCs) from breast cancer patients contain metastasis initiating cells (MIC) which cause lung, liver, and bone metastasis in mice. Baccelli et al further teach that these MIC-containing CTC populations express EPCAM, CD44, CD47 and MET. Bacelli et al additionally demonstrate that in a small patient cohort with tumor metastasis, the population of EPAM+CD44+CD47+MET+ correlated with increased metastasis and low overall survival. Baccelli et al further demonstrate that all of the CTCs in one of the patients expressed both the cancer stem cell marker CD44 and CD47, implying that the MIC-containing CTCs contain cancer stem cells that express CD47. An ordinary skill in the art who had reviewed Lee et al could have come across Baccelli et al and immediately recognize the benefit of employing the morpholino of Lee et al to target the CD47-expressing CSCs in patients with breast cancer. In other words, claims 7,19, and 28 would have been obvious to one of ordinary skill in the art, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Because Lee et al demonstrate that CD47 is highly expressed in liver cancer stem cells, and that the in vivo targeting of CD47 using morpholino for gene silencing is therapeutically effective in liver cancer, as it causes CSCs to lose their stemness and sensitize them to the effect of chemotherapy, but fail to suggest applying the morpholino to CSCs from other cancer cell types such as breast, prostate, colon, etc. Maxhimer et al teach a method that involves indirectly engaging melanoma cancer stem cells and lung cancer stem cells with a morpholino complimentary to CD47. Baccelli et al teach that MIC-containing CTCs contain cancer stem cells that cause bone, liver, and lung metastasis, and show that these MIC express CD47 and CD44. Thus, one would have been motivated to utilize the antisense morpholino, as disclosed by Lee and Maxhimer, to target CD47-overexpressing CSCs in a variety of cancers. There would be a reasonable expectation of success in using antisense morpholino complementary to CD47 to target CD47-expressing CSCs, because doing so would reduce stem cell characteristics and in vivo tumor initiating ability, inhibit tumor growth, reduce metastasis, and sensitize cells to the effect of chemotherapy and radiotherapy.
Regarding claims 20 and 21, Lee et al teach an antisense morpholino oligonucleotide consisting of the exact nucleic acid sequence of SEQ ID NO.70. ( See Supplementary Materials and Methods “ Vivo-morpholino sequences table).
Regarding claims 23-25, Lee et al teach the use of HCC cells and patient derived-xenograft models to test the in vivo therapeutic effects of CD47.(See Fig.6A,B). For example, in the patient derived xenograft animal model, Lee et al teach that the treatment using the morpholino begins once the size of the xenografts reached approximately 6 X 6 mm in size. This reads on claims 23-25. Lee et al show that the CD47 antisense morpholino significantly reduced tumor volumes in a manner approximately 2-fold more potent than the chemotherapy agent doxorubicin (Fig.6B). In addition, Lee et al teach that the CD47 antisense morpholino exerted a synergistic effect with doxorubicin (DOX).
Regarding claim 26, Lee et al teach the combined administration of the morpholino oligonucleotide with an effective amount of the chemotherapy agent doxorubicin into a subject. (See Fig.6A,B).
Regarding claim 27, following the discussion of claim 17 above, Lee in view of Maxhimer renders obvious the use of morpholino complementary to CD47 to reduce stem cell characteristics and the in vivo tumor initiating ability, and to sensitize cells to the effect of chemotherapy and radiotherapy. For the in vitro contact, Lee et al performed a CD47 knockdown experiment using an shRNA approach mediated by a lentiviral vector in HCC cells such as Huh-7, and MHCC-97L. (See Fig.3A). Lee et al teach that the knockdown of CD47 results in fewer and smaller Hepatospheres. (See Fig.3C). Lee et al also teach that the knockdown of CD47 in the HCC cells downregulated the stemness associated genes while increasing cell sensitivity to chemotherapy agents such as cisplatin and doxorubicin. (See supporting table 4, and Fig.3D). Also, for the in vitro contact Lee et al teach the use of HCC cell lines containing a population of both CSC and differentiated fractions. Hence, while Lee et al do not implicitly state the targeting of CSC, the claimed term is presumed to be inherent in Lee’s teachings. This is demonstrated by the teachings, which show that the expression of CD47 in the HCC cells (Huh-7 and MHCC-97L) highly overlaps with that of the TIC stem cell markers such as CD133,CD24, and EpCAM, implying that these cell line contain high population of liver cancer stem cells. (See Fig.1D and supporting Fig.2B).
Lee et al does not teach the in vitro contacting the CSC with an antisense morpholino complementary to CD47. It should be noted that both the antisense morpholino and the shRNA approaches have a reasonable expectation of success when used as a gene silencing tool. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention to use the morpholino over the shRNA approach for the in vitro and in vivo contact to reduce stem cell characteristics and the in vivo tumor initiating ability, and to sensitize cells to the effect of chemotherapy, because Lee et al teach the in vivo use of morpholino for gene silencing is therapeutically effective. It is also well known in the art that morpholinos are preferred over other silencing methods due to their lack of off-target effects, exquisite sequence specificity, complete stability in biological systems, and highly predictable targeting. Thus, one would have a reasonable expectation of success in choosing the morpholino over the shRNA approach for the in vitro and in vivo contacts, because one would know that morpholinos are more effective, specific, and lack off-target effects. See MPEP 2143 (I)(G). Thus, the invention as claimed is unpatentable over the work of the prior art.
Response to Arguments
Applicant's arguments filed 10/08/2025 have been fully considered but they are not persuasive.
Applicants still disagree with the office’s position that the recitation of “ SIRPα-independent differentiation of CSCs by CD47-targeted morpholinos” is an inherent property. Applicant also notes that neither Maxhimer nor Lee provide evidence of a SIRP-α independent mechanism.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because while the office agrees that Applicant has recognized another advantage for contacting the CSCs with the CD47-targeted morpholino, wherein the advantage is represented by the functional outcome of inducing SIRPα-independent differentiation of CSCs, an advantage that was not recognized by prior art at the time the invention was filed; however, according to the MPEP, this functional outcome would flow naturally from following the suggestion of the prior art and cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). This is because Lee et al recognized the benefit of directly contacting liver CSCs with CD47-targeted morpholino and taught the exact active step of the claimed method. An ordinary skill in the art who had reviewed the teachings of Lee et al would immediately recognize the advantage of employing the same morpholino to target CD47-expressing CSCs in a variety of cancer types. The office also agrees with Applicant that neither Maxhimer nor Lee recognized the recited functional outcome. However, according to the MPEP the recited outcome is considered to be inherent in the teachings of Lee et al as it would result from performing the method step, and thus has no patentable weight. For a method claim comprising a functional outcome, it is not required that a prior art would disclose/recognize the functional outcome before a prima facie case of obviousness would be established. While the references do not show a specific recognition of the recited functional outcome, its discovery by appellants is tantamount only to finding an inherent property. When instant claims are directed to a method, for the method claim to be patentable, the claimed instant method must include steps not previously disclosed in the prior art. Upon reviewing the specification, and as discussed above, it appears that the instant method comprises of only one active step (i.e. directly contacting CSCs with CD47-targeted morpholino), which was also taught by Lee et al. The specification contains no information indicating that the instant method differs from the method taught by Lee et al. According to the MPEP “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention”. In conclusion, for the invention to be patentable, the claimed method must involves additional structural limitations that would account for such a difference (for example, the presence of additional constituents, specific type of administration or a narrow concentration range where this effect is seen).
As per Applicant’s argument against Maxhimer et al that a skilled person upon reviewing Maxhimer et al would not conclude that stem cells are required for the observed responses in the lung cancer or melanoma tumor models. Applicant’s arguments have been carefully considered and found persuasive. For this reason, the rejection of the claims under 35 U.S.C. 102(a) (1) 102 as being anticipated by Maxhimer et al is withdrawn.
Conclusion
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 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638