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 .
Status of Application, Amendments and/or Claims
The amendment and Applicant’s arguments, filed 30 September 2025, have been entered in full. Claims 11-16 are withdrawn from consideration as being drawn to a non-elected invention. Claim 10 is canceled. Claims 1, 3, 4, 6-9 are amended. New claims 17-19 are added. Claims 1-9, 17-19 are under examination.
Withdrawn Objections And/Or Rejections
The objection to the specification due to sequence deficiencies, as set forth at pages 2-5 of the previous Office Action (31 March 2025), is withdrawn in view of Applicant’s arguments (30 September 2025).
The rejection to claims 1-10 under 35 U.S.C. 101 because the claimed invention
is directed to a judicial exception without significantly more, as set forth at pages 5-9 of the previous Office Action (31 March 2025), is withdrawn in view of the amendment (30 September 2025).
The rejection to claim 6 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth at pages 9-10 of the previous Office Action (31 March 2025), is withdrawn in view of the amendment (30 September 2025).
The rejection to claims 1-10 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement, as set forth at pages 10-15 of the previous Office Action (31 March 2025), is withdrawn in view of the amendment (30 September 2025).
The rejection to claims 1-10 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description, as set forth at pages 15-18 of the previous Office Action (31 March 2025), is withdrawn in view of the amendment (30 September 2025).
MATTER OF RECORD
All of the pending rejections are withdrawn due to the amendment. Therefore, Applicant’s presented arguments will not be addressed.
Applicant is reminded of the species election of PIF species SEQ ID Nos. 20, 22-25. The Examiner notes to Applicant that elected species SEQ ID NO:20 and SEQ ID NO:22 are free of the prior art. Please see the New Rejections/Objections below.
NEW CLAIM REJECTIONS/OBJECTIONS
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 should recite, “..exposing a second sample from a second subject..”. (see line 13). Appropriate correction is required.
Claim Rejections-35 USC § 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph
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.
Claim 2 is 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 2 recites the limitation "..wherein the PIF or analog thereof..". Claim 2 depends from claim 1. There is insufficient antecedent basis for the limitation “or analog thereof” in the claim.
Claim Rejections-35 USC § 103
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.
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.
1. Claims 1, 2, 9 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Barnea (WO 00/63675; published October 26, 2000) in view of Barnea (WO 2005/040196; Barnea ‘196; published May 6, 2005), Barnea (US 2009/0081225; Barnea ‘225; published March 26, 2009) as evidenced by Heath, W. (The secret of CD45, Trends in Immunology, Vol. 22, No. 3, page 123; March 2001).
The instant claims are drawn to detecting the binding of preimplantation factor (PIF) to immune cells from samples of subjects who are suspected of having recurrent pregnancy loss (RPL) or endometriosis compared to control samples.
The Examiner notes that limitations such as “comparing” and “determining” are not active method steps.
Barnea teaches diagnosis of endometriosis by detecting increased levels of endometriosis factor (EF) in sera and other biological fluids of the subject. The level of EF in the sample can be assayed using a lymphocyte/platelet binding assay. Barnea teaches serum from subjects having endometriosis contains an elevated levels of a factor that decreases PIF activity. Barnea teaches PIF activity can be detected by its ability to increase the binding of platelets to lymphocytes. Barnea teaches that in the presence of EF, PIF mediated platelet/lymphocyte binding is decreased (page 1).
Barnea teach lymphocyte/platelet binding assays have been used to detect preimplantation factor (PIF) in the serum of pregnant females as described in U.S. Patent No. 5,645,003. The presence of PIF was shown to be a positive indicator of pregnancy and was found to be useful in predicting the spontaneous loss of pregnancies. Barnea teaches that assays for PIF activity could be used as a diagnostic tool for endometriosis. Such an assay is based on PIF mediated enhancement of lymphocyte/platelet binding activity. Barnea teaches that this is in contrast to the present invention which provides methods for diagnosing endometriosis in a subject based on EF mediated reduction in binding of lymphocytes to platelets (page 3).
Barnea teaches that the detection of EF in a body fluid from a subject can be accomplished by measuring the inhibition of PIF activity using a lymphocyte/platelet binding assay. The assay comprises (a) removal of cells, cell debris and tissue elements from a body fluid sample of a subject; (b) providing blood lymphocytes containing platelets; (c) providing PIF activity; (d) providing an anti-CD2 antibody; (e) admixing said body fluid, lymphocytes containing platelets, PIF activity and anti-CD2 antibody; and (f) determining in the admixture the percentage of lymphocytes bound to platelets; whereby a percentage significantly lower than the percentage in a normal control sample or in the foregoing mixture lacking the body fluid indicates the presence of EF in the serum. Barnea teaches in Figure 1, that the percentage of lymphocyte binding decreases from 18% to less than 12% depending on the amount of endometriosis serum added (page 7). Endometriosis serum decreases PIF activity, which results in decreased PIF mediated lymphocyte/platelet binding (applies to claim 1).
Lymphocytes are white blood cells that express CD45, as evidenced by Heath. Types of lymphocytes include B cells, T cells and natural killer cells (NK) (The secret of CD45, Trends in Immunology, Vol. 22, No. 3, page 123; March 2001)(applies to claim 1).
Barnea does not teach PIF peptide sequences.
Barnea ‘196 teaches a PIF peptide sequence MVRIKPGSANKPSDD, that is 100% identical to instant SEQ ID Nos: 23, 24 and 25 (page 26, Table 1, SEQ ID NO:1) (applies to claim 1). Barnea ‘196 teaches PIF (SEQ ID NO:1) binds to lymphocytes, which forms rosettes with platelets in the lymphocyte/platelet binding assay (page 28, para 0064 and Figure 1).
Barnea ‘225 teaches PIF biological activity is exerted by specific binding to receptors present on the several white cell lineages (abstract). Barnea ‘225 teaches that these cells may be peripheral blood mononuclear cells (PBMC), T cells, B cells, monocytes or macrophages (para 0019). Barnea ‘225 teaches PIF binds to human lymphocytes (para 0025). Barnea ‘225 teaches PIF peptides can be immobilized to a solid support (paras 0030 and 0095)(applies to claim 2).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of detecting and quantifying lymphocyte/platelet binding comprising exposing a first sample from a first subject suspected of having endometriosis to PIF activity and lymphocytes containing platelets and comparing it to a second sample from a second subject that does not have endometriosis wherein the second sample is exposed to PIF activity and lymphocytes containing platelets, as taught by Barnea, by substituting the PIF activity with a PIF peptide sequence, as taught by Barnea ‘196, wherein PIF peptides are attached to a column, as taught by Barnea ‘225, wherein binding of PIF to CD45+ cells is detected and quantified.
One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons.
Barnea teaches that PIF activity is based on PIF mediated enhancement of lymphocyte/platelet binding activity. Barnea teaches endometriosis serum decreases PIF activity, which results in decreased PIF mediated lymphocyte/platelet binding. Barnea ‘225 teaches PIF biological activity is exerted by specific binding to inducible receptors present on the several white cell lineages. Lymphocytes are white cells that express CD45, as evidenced by Heath. Based on the teachings, it would be obvious to have less binding of PIF to cells expressing CD45 in endometriosis samples compared to samples from subjects who do not have endometriosis (applies to claims 1, 9 and 19). Lastly, using a PIF peptide sequence that mediates enhancement of lymphocyte/platelet binding activity, as taught by Barnea ‘196, avoids the need of isolating PIF activity from pregnant women.
2. Claims 1, 2, 8 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Barnea (WO 00/63675; published October 26, 2000) in view of Barnea (WO 2005/040196, Barnea ‘196; published May 6, 2005), Gagne et al. (Blood leukocyte subsets are modulated in patients with endometriosis. Fertility and Sterility, Volume 80/No.1:43-53, 2003) and Barnea (US 2009/0081225; Barnea ‘225; published March 26, 2009).
The instant claims are drawn to detecting the binding of preimplantation factor (PIF) to immune cells from samples of subjects who are suspected of having recurrent pregnancy loss (RPL) or endometriosis compared to control samples.
The Examiner notes that limitations such as “comparing” and “determining” are not active method steps.
Barnea teaches diagnosis of endometriosis by detecting increased levels of endometriosis factor (EF) in sera and other biological fluids of the subject. The level of EF in the sample can be assayed using a lymphocyte/platelet binding assay. Barnea teaches serum from subjects having endometriosis contains an elevated levels of a factor that decreases PIF activity. Barnea teaches PIF activity can be detected by its ability to increase the binding of platelets to lymphocytes. Barnea teaches that in the presence of EF, PIF mediated platelet/lymphocyte binding is decreased (page 1). Barnea teach lymphocyte/platelet binding assays have been used to detect preimplantation factor (PIF) in the serum of pregnant females as described in U.S. Patent No. 5,645,003. The presence of PIF was shown to be a positive indicator of pregnancy and was found to be useful in predicting the spontaneous loss of pregnancies. Barnea teaches that assays for PIF activity could be used as a diagnostic tool for endometriosis. Such an assay is based on PIF mediated enhancement of lymphocyte/platelet binding activity. Barnea teaches that this is in contrast to the present invention which provides methods for diagnosing endometriosis in a subject based on EF mediated reduction in binding of lymphocytes to platelets (page 3). Barnea teaches that the detection of EF in a body fluid from a subject can be accomplished by measuring the inhibition of PIF activity using a lymphocyte/platelet binding assay. The assay comprises (a) removal of cells, cell debris and tissue elements from a body fluid sample of a subject; (b) providing blood lymphocytes containing platelets; (c) providing PIF activity; (d) providing an anti-CD2 antibody; (e) admixing said body fluid, lymphocytes containing platelets, PIF activity and anti-CD2 antibody; and (f) determining in the admixture the percentage of lymphocytes bound to platelets; whereby a percentage significantly lower than the percentage in a normal control sample or in the foregoing mixture lacking the body fluid indicates the presence of EF in the serum. Barnea teaches in Figure 1, that the percentage of lymphocyte binding decreases from 18% to less than 12% depending on the amount of endometriosis serum added (page 7). Endometriosis serum decreases PIF activity, which results in decreased PIF mediated lymphocyte/platelet binding (applies to claim 1).
Barnea does not teach PIF peptide sequences. Barnea does not teach CD3+ cells.
Barnea ‘196 teaches a PIF peptide sequence MVRIKPGSANKPSDD that is 100% identical to instant SEQ ID Nos: 23, 24 and 25 (page 26, Table 1, SEQ ID NO:1) (applies to claim 1). Barnea ‘196 teaches PIF (SEQ ID NO:1) binds to lymphocytes, which forms rosettes with platelets in the lymphocyte/platelet binding assay (page 28, para 0064 and Figure 1).
Gagne et al. teach that the present study examines whether immune cell populations are altered in the blood of patients with endometriosis (abstract). Gagne et al. discloses that Wu et al. report a modest, but significant, decrease in the proportion of CD3+ T lymphocytes expressing either CD69 or CD25 activation marker in the blood of patients with endometriosis compared with normal controls (page 44, left column, 2nd full paragraph). Gagne et al. teach that the proportion of blood leukocytes expressing surface markers for T (CD3), B lymphocytes (CD20), monocytes (CD14), or NK cells (CD56) were compared by flow cytometric analysis in 175 patients with endometriosis and 131 controls (page 44, left column, 3rd full paragraph). Gagne et al. teach that the proportion of T lymphocytes (CD3-positive cells) was shown to be slightly but significantly decreased in the blood of endometriosis samples compared with controls (page 48 and Table 4)(applies to claim 1).
Barnea ‘225 teaches PIF biological activity is exerted by specific binding to receptors present on the several white cell lineages (abstract). Barnea ‘225 teaches that these cells may be peripheral blood mononuclear cells (PBMC), T cells, B cells, monocytes or macrophages (para 0019). Barnea ‘225 teaches PIF binds to human lymphocytes (para 0025). Barnea ‘225 teaches PIF peptides can be immobilized to a solid support (paras 0030 and 0095)(applies to claim 2).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of detecting and quantifying lymphocyte/platelet binding comprising exposing a first sample from a first subject suspected of having endometriosis to PIF activity and lymphocytes containing platelets and comparing it to a second sample from a second subject that does not have endometriosis wherein the second sample is exposed to PIF activity and lymphocytes containing platelets, as taught by Barnea, by substituting the PIF activity with a PIF peptide sequence, as taught by Barnea ‘196, wherein PIF peptides are attached to a column, as taught by Barnea ‘225, wherein binding of PIF to CD3+ cells is detected and quantified.
One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons.
Barnea teaches that PIF activity is based on PIF mediated enhancement of lymphocyte/platelet binding activity. Barnea teaches endometriosis serum decreases PIF activity, which results in decreased PIF mediated lymphocyte/platelet binding. Barnea ‘225 teaches PIF biological activity is exerted by specific binding to inducible receptors present on the several white cell lineages, which include T cells.
Gagne et al. teach that the proportion of T lymphocytes (CD3-positive cells) was shown to be slightly but significantly decreased in the blood from endometriosis subjects compared with controls. Based on the teachings, it would be obvious to have less binding of PIF to cells expressing CD3+ in endometriosis samples compared to samples from subjects who do not have endometriosis (applies to claims 1, 8 and 18). Lastly, using a PIF peptide sequence that mediates enhancement of lymphocyte/platelet binding activity, as taught by Barnea ‘196, avoids the need of isolating PIF activity from pregnant women.
3. Claims 1, 3-7 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Barnea et al. (Preimplantation factor (PIF) orchestrates systemic anti-inflammatory response by immune cells: effect on peripheral blood mononuclear cells. American Journal of Obstetrics and Gynecology 207:313.e1-11, October 2012).
The instant claims are drawn to detecting the binding of preimplantation factor (PIF) to immune cells from samples of subjects who are suspected of having recurrent pregnancy loss (RPL) or endometriosis compared to control samples.
The Examiner notes that limitations such as “comparing” and “determining” are not active method steps.
Barnea et al. teach a PIF peptide sequence MVRIKPGSANKPSDD that is 100% identical to instant SEQ ID Nos: 23, 24 and 25 (page 313.e3, first column, Figure 2)(applies to claim 1). Barnea et al. teach nonpregnant patients who underwent infertility treatment signed standard informed consent. Blood was drawn as part of the work-up process with the use of excess specimen without identifiers (n=7)(i.e. suspected of recurrent pregnancy loss, RPL). Barnea et al. teach additional samples were obtained from 18 male volunteers. Twelve nonpregnant and 13 pregnant women in the first trimester were also studied. Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood. PBMCs were incubated with FITC-PIF, FITC-PIFscrambled and size-matched irrelevant peptide along with antibody cocktail (anti-CD13, CD3, CD4, CD8, CD19, CD56). Barnea et al. teach that in certain experiments, PBMCs were stimulated with phytohemagglutin. Barnea et al. teach cells were stimulated with anti-CD3 antibody or anti-CD3/anti-CD28 antibody or heterologous mixed lymphocyte reaction (MLR) that contained PIF or PIFscr (page 313.e3). Barnea et al. teach binding data was analyzed. Regression analysis was used to determined FITC-binding to PBMC lineages (page 313.e4, Statistical analysis, applies to claims 3 and 4). Barnea et al. teach PIF interactions with PBMC using FITC-PIF. Barnea et al. teach the use of unstimulated PBMC for flow cytometry in Figure 3. Barnea et al. teach that FITC-PIF binds all unstimulated CD14+ cells and minimally to CD4+ and CD8+ cells (Figure 3 and applies to claim 5).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of detecting and quantifying immune cells that bind to PIF comprising exposing samples from pregnant women, nonpregnant patients who underwent infertility treatment, nonpregnant women and males, as taught by Barnea et al., by using the assay to determine that the number of CD14+ cells bound to PIF in samples from nonpregnant patients who underwent infertility treatment is increased compared to the number of CD14+ cells bound to PIF in samples from subjects.
One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons.
Barnea et al. teach in Figure 3C the percentage of FITC-PIF binding. In Figure 3C, FITC-PIF binds all CD14+ cells from pregnant patient samples. Figure 3C also demonstrates some binding in the non-pregnant samples, albeit less binding when compared to pregnant sample and thus appears to account for the nonpregnant females who underwent infertility, wherein the lowest percentage of binding from the non-pregnant samples account for the nonpregnant females and males. Based on the teachings, it would be obvious that a sample from a subject suspected of having RPL would have a higher number of CD14+ cells binding to PIF (first sample) compared to a sample from a subject that does not have RPL (second sample) (applies to claims 6, 7 and 17).
Conclusion
No claims are 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.
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/R.M.D/Examiner, Art Unit 1647 1/8/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647