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 OFFICE ACTION
This Office Action is in response to the papers filed on 26 March 2026.
CLAIMS UNDER EXAMINATION
Claims 1, 3, 5, 8-9, 11 and 15 have been examined on their merits.
PRIORITY
The Application is a continuation of PCT/US2019/053232 filed on 26 September 2019.
WITHDRAWN REJECTIONS
The arguments made in the response filed on 26 March 2026 are acknowledged. The rejection made under 35 USC 101 has been withdrawn due to claim amendment.
The rejections of claim 5 under 35 USC 112(b) and (d) are have been withdrawn due to claim amendment.
REJECTIONS
New grounds of rejection have been necessitated by claim amendment.
Claim Rejections - 35 USC § 112
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 3 and 11 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.
Regarding claim 3: claim 1 has been amended to recite 1) “isolating one or more CD34+CD164high cells” and 2) “isolating CD34+CD164 high early stage progenitor cells”. Claim 3 has been amended to recite “the CD34+CD164high isolation enriches for the early stage hematopoietic progenitor cells”. It is unclear which isolation step in the base claim 3 is referring to. The metes and bounds of the claim is unclear. Appropriate correction is required.
Regarding claim 3: the claim has been amended to recite “the early stage hematopoietic progenitor cells”. The base claim recites “primitive hematopoietic stem/progenitor cells”, “early stage progenitor” and “early stage progenitor cells”. There is a lack of antecedent basis for “early stage hematopoietic progenitor cells”. Appropriate correction is required.
Regarding claim 11: the claim has been amended to recite “the isolating comprises contacting the cells…”. claim 1 has been amended to recite 1) “isolating one or more CD34+CD164high cells” and 2) “isolating CD34+CD164 high early stage progenitor cells”. It is unclear which isolating step claim 11 is referring to. The metes and bounds of the claim are unclear. Appropriate correction is required.
RESPONSE TO APPLICANT
The arguments made in the response filed on 26 March 2026 are acknowledged.
Argument: The arguments state the claims have been amended to overcome the rejections made in the prior Office Action.
Response: The amended claims raise new issues under 35 USC 112(b). New grounds of rejection have been necessitated by claim 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.
Claim 3 is 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.
Claim 3 recites “greater than about 70%, 80% or 90%”. The base claim recites “60%”. The specification does not define the term “about”. The claim is not further limiting because “about 70%” can include values lower than 60%.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims complies with the statutory requirements.
RESPONSE TO APPLICANT
The arguments made in the response filed on 26 March 2026 are acknowledged.
Argument: The arguments state the claims have been amended to overcome the rejections made in the prior Office Action.
Response: Claim 3 recites “about 70%”. Neither the claims or specification define the term “about”. Therefore it may include values lower than the 60% recited in claim 1. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3, 5, 8-9, 11 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Watt et al. (previously cited; CD164, a Novel Sialomucin on CD34+ and Erythroid Subsets, Is Located on Human Chromosome 6q21. Blood, Vol 92, No 3 1998, 849-866) in view of McGuckin et al. (previously cited; Colocalization Analysis of Sialomucins CD34 and CD164. Stem Cells 2003; 21: 162-170) and Savelieff et al. (previously cited; Fluorescence-Activated Cell Sorting for Cell-Based Therapies 31 March 2019).
Watt teaches the CD164 epitope is expressed on very primitive hematopoietic CD34+ progenitor cells (Abstract; page 850, left column, last paragraph). Watt analyzes expression of CD164 on CD34+ cells from cord blood and bone marrow (page 850, left column, third paragraph). Cells are isolated from bone marrow, cord blood and peripheral blood samples (page 850, right column, second paragraph). CD34+ cells are isolated using Magnetic-Activated Cell Sorting (MACS) and cultured (same cited section). Cells are stained with CD164 antibodies and analyzed using a FACS flow cytometer (see Figure 3).
Claim 1 recites the level of CD164 in an early stage progenitor is at least about 103 to 104, whereas the level of CD164 is about 102 in a late stage progenitor cell. The specification states “about” “is understood as within a range of normal tolerance in the art” ([0056]). While the specification states “an example is within 2 standard deviations of the mean” and “about can be: within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value” these are examples. Therefore “about 103 to 104” includes CD164 levels lower than 103 , and “about 102” includes CD164 levels higher and lower than 102. Figure 3 illustrates CD164+ cells that are about 102, and cells that are about 103 (see page 854, left column). Therefore the art is interpreted to teach early and late stage progenitor cells as claimed.
The following is also noted:
The PG Pub of the specification states “Isolate denotes a degree of separation from original source or surroundings” ([0038]).Watt harvests cells from human bone marrow, cord blood and peripheral blood specimens. As evidenced by Watt, the harvested cells contain CD34+CD164high cells (about 103). Obtaining the specimens from a subject is interpreted to read on isolating one or more CD34+CD164high cells.
Watt teaches mature peripheral blood cells showed only low or negligible levels of CD164 expression (page 852, right column, lines 14-23). Watt teaches CD164 mediates the adhesion of CD34+ hematopoietic progenitor cells to bone marrow stroma. Essentially all committed myeloid and erythroid progenitors and their immature precursors were present in the CD164+ population.
Watt isolates one or more CD34+CD164high cells.
Watt cultures cells. Therefore the cells are expanded.
Watt characterizes and compares the levels of CD164 by FACS and illustrates expression of about 102 and about 103.
The deficiency of Watt is that it does not teach isolating CD34+CD164high early stage progenitor cells from the expanded cells to obtain a population comprising 60% of said cells.
McGuckin et al. “investigated two sialomucin adhesion molecules, CD34 and CD164, both considered to be important in transplantation and engraftment” (see page 166, right column, first three lines). McGuckin et al. teach CD34 is a marker of hemopoietic stem and progenitor cells during early hemopoiesis, and is used as a marker for hemopoietic cell harvest protocols (Abstract; page 163, left column, third paragraph). CD164 is also expressed on early hematopoietic populations (Abstract).
The art teaches “flow cytometric protocols are employed to identify and characterize hemopoietic stem/progenitor populations before transplantation (first sentence of Abstract).
Using FACS, the art teaches “CD34 and CD164 sialomucins were coexpressed on a discrete CD34+ and CD164+ cell subset…of MNCs in CB and BM” (see page 164, right column, first paragraph of RESULTS”). It is of note the art also discloses CB and BM CD34+CD164+ cells which also express AC133 (same section). McGuckin teaches “our existing fluorescence-activated cell sorting data in this area …has indicated that CD34+CD38- HSPCs express higher levels of AC133 and CD164 than the more mature CD34+CD38+ group” (page 169, left column, last paragraph).
The art also teaches the following:
HSPC maturation level might influence CD34 and CD164 membrane distribution (page 169, left column, last paragraph). CD34+CD164+ cells which are highly enriched with the AC133+ have high proliferation potential and increased long-term culture initiating cell frequencies (page 169, right column, first paragraph).
CD164 may functionally facilitate CD34+ cell adhesion to bone marrow stroma (Abstract; page 163, left column, fourth paragraph). The art teaches a related role for CD34 and CD164 in homing and adhesion to BM stroma and regulating CD34+ growth and differentiation (page 168, last sentence of left column bridging right column). The art teaches a functional link between these sialomucins and should be considered in the transplantation arena (Abstract).
Savelieff et al. disclose fluorescence-activated cell sorting (FACS), is a specialized flow application that, in addition to analyzing the fluorophore content and biomarkers on single cells, can sort them based on the desired phenotype. One potential therapeutic application is for collected cells to be expanded ex vivo and reinfused into the patient as cell-based therapies. In addition, the ability to serially analyze single cells can lead to a high purity of sorted cells. This is important for cell-based therapies, which must be free of contaminating harmful cells or therapeutically ineffective cells. (See second and third paragraphs of page 3).
It would have been obvious to isolate CD34+CD164high cells taught by Watt. McGuckin teaches CD34+ cells with higher expression of CD164+ are immature, have high proliferation potential, increased long-term culture initiating cell frequency and facilitate adhesion. The skilled artisan would isolate cells with the claimed phenotype to obtain a population of cells suitable for transplantation and engraftment. One would have had a reasonable expectation of success since both references teach FACS to sort (hence, isolate) cells based on CD164 expression. One would have expected similar results since both references are directed to progenitor cells which express CD34 and CD164.
It would have been obvious to use FACS sorting to obtain a population comprising 60% of the claimed cells. Watt uses FACS to sort cells and Savelieff teaches FACS can be used to sort cells based on a desired phenotype to obtain a high purity of desired cells. One would have had a reasonable expectation of success since Savelieff teaches cells analyzed by FACS can be expanded. One would have expected similar results since all of the references are directed to FACS analysis of cells. Therefore claim 1 is included in this rejection.
It would have been obvious to enrich for a population greater than about 70% for the reasons stated in the rejection of claim 1. Therefore claim 3 is included in this rejection.
Watt teaches cells that are about 102 and about 103 (supra). Therefore claim 5 is included in this rejection.
Watt teaches the CD34+CD164(103B2/9E10)lo/− cell population in bone marrow consisted mainly of CD19+ B-cell precursors, suggesting that the most immature B-cell subset in bone marrow is CD164− (see page 860, left column, second paragraph).
It would have been obvious to exclude B cell progenitors. Watt teaches these cells have low/no CD164. One would exclude them to obtain a subset of cells with high proliferation potential, increased long-term culture initiating cell frequency that are capable of bone marrow adhesion. One would have had a reasonable expectation of success since Savelieff teaches cells can be sorted to obtain a desired phenotype. Therefore claim 8 is included in this rejection.
Watt does not select any cells with the markers recited in claim 9. Therefore claim 9 is included in this rejection.
Watt teaches the uses a CD34 antibody and a CD164 antibody (supra; see page 850, right column, last paragraph). FACS is an abbreviation of “Fluorescence-Activated Cell Sorting”. Therefore cells are sorted out. Therefore claim 11 is included in this rejection.
Watt analyzed CD38 expression (see page 858, left column, second paragraph). Therefore claim 15 is included in this rejection.
Therefore Applicant’s invention is rendered obvious as claimed.
APPLICANT’S ARGUMENTS
The arguments made in the response filed on 26 March 2026 are acknowledged.
Argument 1: The Applicant makes arguments directed to “Watt 2” (2000). The Applicant argues this reference indicates that even enriching for CD34+CD164+AC133+ cells
would not reach the early stage progenitor cells recited in the claims, "wherein the level of CD164 in an early stage progenitor is at least about 10³ to 10⁴".
The Applicant alleges CD34+AC133+ cells have CD164 expression levels of approximately 11 or 12, which is even lower than the CD164 expression levels that the present claims assign to late stage progenitors. The Applicant states looking solely at CD34+CD164+AC133+ cells, Watt 2 teaches that these cells have a median expression level of 259±128 for CD164. This is far from the "at least about 10³" (i.e., 1,000) levels of CD164 recited in the claims for early stage progenitors.
Response: The rejection is not based on the Watt 2000 reference. The reference is based on the teachings in the Watt 1998 disclosure. The arguments do not address Watt 1998 or McGuckin.
Regarding Watt 2000 (Watt 2): The Applicant appears to argue the cells taught in Table 1 of Watt 2000 are the same as those in Watt 1998. Table 1 of Watt 2000 is directed to fetal liver cells. Watt 2000 analyzes and compares expression and fluorescence intensity for three different CD164 epitopes: 105A5 (class I epitope), 103B2/9E10 (class II epitope) and N6B6 (class III epitope) (see Table 1; also see page 3114, left column, third paragraph). Table 1 also compares AC133+ and AC133lo. Watt 2000 teaches epitope expression differs in cells from bone marrow, cord blood and fetal liver cells (see page 3116, right column, first paragraph; see Figure 2). Watt 2000 teaches the following: (see page 3116, right column, first paragraph):
we show that the CD164class I and II epitopes are uniformly expressed on the most
primitive hematopoietic progenitor cells. However, they are differentially
and often reciprocally expressed in postnatal tissues. This is particularly evident in lymphoid tissues and in colon. These CD164 class I and II epitopes may have distinct functions on different postnatal cell types, perhaps being involved in blood cell
homing, trafficking, and recirculation.
The Applicant’s arguments directed to Watt 2000 are based on expression in cell subsets from liver cells with specific CD164 and AC133 epitopes which are not claimed.
In contrast to Table 1 of Watt 2000 (which analyzes fetal liver cells and specific CD164 epitopes), the Watt 1998 reference relied upon is analyzes CD164 in cells from cord blood and bone marrow. Therefore the arguments are not persuasive.
Argument 2: The Applicant argues the Watt 2000 reference teaches lower levels of CD164 expression.
Response: The rejections are based on the teachings of the Watt 1998 disclosure. The art teaches CD164 expression which reads on the claimed levels. The argument is not persuasive.
Argument 3: The Applicant argues Savlieff does not teach sorting the claimed cells and markers.
Response: The Savlieff reference is not relied upon to teach the claimed cells and markers. Savlieff teaches FACS can be used to isolate a desired population and quantity of cells. The argument is not persuasive.
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 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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