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 .
Response to Election
Claims 1-26 and 30-34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election of Group II (Claims 27-29) was made without traverse in the reply filed on 03/06/2026.
After a search of the prior art, there was not a search burden for the HSPC species recited in Claim 29.
Claims 27-29, including all species, are herein examined.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper."
The information disclosure statement (IDS) submitted on 01/11/2024 and 05/16/20204 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claim 29 is objected to because of the following informality: “HSC” is an acronym which stands for hematopoietic stem cell; “MMP1-4” is an acronym which stands for “multipotent progenitor types 1, 2, 3, and 4”; “CMP” is an acronym which stands for “common myeloid progenitor”; “GMP” is an acronym which stands for “granulocyte-monocyte progenitor”; and “MEP” is an acronym which stands for “megakaryocyte-erythroid progenitor” and needs to be spelled out in the claims, at least once in the first occurrence.
Claim Rejections - 35 USC § 112(b)
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 27-29 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.
Claims 27-29 are rejected as indefinite because expansion of hematopoietic stem and progenitor cells (HSPCs) could be interpreted in two different ways and therefore the metes and bounds of the claim are unclear. First, expansion could occur in vivo by transplanting HSPCs, which were previously administered recombinant EGFL7 protein (rEGFL7), into a subject, for example, to assist in blood renewal. It could also be interpreted as expansion ex vivo, for example, to make a source of stem cells ready for transplantation. For the purposes of examination, based on the specification (pg. 62, Example 3) claim 27 will be interpreted as ex vivo expansion of HSPCs. Dependent claims 28 and 29 are included in this rejection because they do not resolve the aforementioned issue.
Claims 27-29 are further rejected as indefinite because expansion is not defined in the specification and it is unclear if a certain threshold of expansion is required in order for the limitation to be reached. For the purposes of examination, expansion itself will be interpreted as any increase in number of HSPCs through self-renewal (i.e. self-replication). Dependent claims 28 and 29 are included in this rejection because they do not resolve the aforementioned issue.
Claims 27-29 are further rejected as indefinite for “administering to a hematopoietic stem and progenitor cell” because this phrase is unclear. Hematopoietic stem and progenitor cells are often referred to as a single category (HSPCs). Therefore, it is unclear if the claim requires: (1) administration to a single cell type within this category (i.e. HSCs) or (2) if the claim requires administration to both a hematopoietic cell and a progenitor cell (i.e. an LT-HSC and an MPP). For the purposes of claim interpretation, based on convention within the art and the specification, the former interpretation will be used. Dependent claims 28 and 29 are included in this rejection because they do not resolve the aforementioned issue.
Claim 28 and 29 is rejected as indefinite because the metes and bounds of "stem cell potential" are unclear and the phrase is not defined in the specification. Stem cells are defined by 1) their ability to self-renew and 2) their ability to differentiate into different cells (pg. 128, left side, lines 1-4). "Stem cell potential" could be interpreted as a cell that has potential to self-renew or differentiate, rather than a cell that has ability to do both. However, this is not a reasonable interpretation because by definition, a stem cell must possess both of these abilities. Therefore, the broadest reasonable interpretation of “stem cell potential” is the ability of a cell to both self-renew and differentiate into another cell type(s). Furthermore “a loss” of stem cell potential is not defined in the specification. Under broadest reasonable interpretation, “a loss” includes both complete removal, as well as diminishment of or reduction in stem cell potential, such as a diminished capacity to self-renew. Claim 29 is rejected in this rejection because it does not resolve the aforementioned issue.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(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.
Claims 27-29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because, regarding Claims 27 and 29, the specification, while being enabling for ex vivo expansion of normal HSCs by administering a rEGFL protein, does not reasonably provide enablement for expansion of any HSPC from any source. Regarding claim 28, the specification is not enabling for the expansion without a loss of stem potential for any HSPCs from any source. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
MPEP § 2164.01(a) states that there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors include, but are not limited to:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
Claim 27 recites expansion of HSPCs comprising administering rEGFL7 to HSPCs. Claims 28 and 29 recite that expanding HSPCs does not result in a loss of stem cell potential and that the cell populations are HSPCs selected from: HSCs, MPPs, CMPs, GMPs, or MEPs.
The breadth of the claims and the nature of the invention:
The claims and nature of the invention are extremely broad, while what is enabled is narrow and specific. Under broadest reasonable interpretation, Claim 27 recites expansion of HSPCs from any source via any method of administration and any amount of rEGFL7.
Furthermore, regarding Claim 28, maintaining stem cell potential requires that cells expanded by administration of a recombinant EGFL7 protein maintain their ability to self-renew and differentiate into different cell types.
Claim further limits Claims 27 and 28 to specific HSPC cell populations, but still includes the vast majority of stem and progenitor cell types in the HSPC lineage.
The state and level of predictability of the prior art:
Regarding the source of HSPCs, the state of the art is more predictable for expansion of HSPCs obtained from cord blood cells (CBs), but less so for bone marrow or mobilized peripheral blood stem cells (mPBSCs). Dahlberg et al., 2011 (instant PTO-892) teaches that HSPC expansion from CBs is more successful, potentially due to inherent differences in the cells (Dahlberg, pg. 6083, right side, second paragraph). Furthermore, under broadest reasonable interpretation, the source of the instant HSPCs could be taken directly from cancer patients; Douay et al., 2001 (see instant PTO-892) teaches that in this embodiment, purging of malignant cells would be an essential step in HSPC expansion (pg. 343-344, “Purging of Malignant Cells” Section). Therefore, the source of the cells is directly related to the success and functionality of HSPC expansion.
Regarding the method of expansion and administration of the recombinant protein, the state of the art teaches that there are a variety of variables that affect the success of ex vivo expansion of HSPCs, including, CD34+ cell purity, initial cell concentration, and the duration of culture (Douay, abstract). Moreover, the concentration of the growth factor administered to HSPCs is known in the art to affect in vitro expansion outcomes (Jönsson et al., 1998, see PTO-982, abstract). These sources teach numerous factors that have a direct impact on expansion success, particularly for cell types other than HSCs (i.e. CMPs, GMPs, MEPs).
With that being said, regarding claim 29, the state of the art does provide support for ex vivo expansion of CMPs, GMPs, and MEPs, using the administration of various other cytokines or growth factors. For example, Pietras et al., 2015, (see instant PTO-892) teaches that in vitro expansion is possible for MPPs, CMPs and GMPs. Altogether, the state of the art demonstrated that ex vivo expansion of the HSCs, MPPs, CMPs, GMPs, or MEPs is possible with some growth factors, but not necessarily with rEGFL7.
Regarding Claim 28, given the state of the art, the specification is not enabling for expansion of HSPCs by administering rEGFL7 without a loss of stem cell potential. Walasek et al., 2012 (see instant PTO-892) teaches that symmetrical cell division, where stem cells differentiate and lose their stem cell potential, usually occurs in ex vivo culture (Fig 1). Furthermore, Beate et al., 2014 (see instant PTO-892) teaches that HSPC expansion with EGFL7 protein results in differentiation. Therefore, one of ordinary skill in the art would expect that EGFL7 causes a loss of stem cell potential. Since there is no evidence to suggest that the instant recombinant EGFL7 protein is functionally different from the EGFL7 protein administered by Beate, one of ordinary skill in the art would expect the instant recombinant protein to also cause differentiation and a loss of stem cell potential.
The amount of direction provided by the inventor and existence of working examples:
Regarding the source of HSPCs and method of rEGFL7 protein administration, the working examples are only drawn toward expansion of normal CD34+ cells from cord blood cells (pg. 62, line 18). CD34+ is used in the art as a marker to sort for HSCs (X, 1999, see PTO-892, abstract). No other starting cell population (i.e. CMPs) or sources of HSPCs (i.e. peripheral blood) were tested. The specification teaches that stimulation of rEGFL7 led to expansion of CD34+ CB cells (Fig. 11). However, this was only conducted at a single concentration of recombinant protein and a single concentration of starting cell population (pg. 8, lines 5-20). Therefore, the specification does not provide adequate guidance for the full breadth of claims 27 and 29, given the numerous factors outlined above that affect HSPC expansion.
Furthermore, the primary Colony Forming Unit analysis (Fig. 12, top panel), demonstrates that the vast majority of cells differentiated in vitro, as indicated by the low number of GEMM colonies, which represents the most primitive and multipotent category of cells, in contrast to the other colony categories, which represent more differentiated cell types. Thus, the specification does not disclose how one of ordinary skill in the art could administer rEGFL7 without a loss of stem cell potential.
Conclusion:
Given the state and unpredictability of the art, breadth of the claims, and amount of direction provided, the disclosure is not sufficient to bridge what is known in the art and the scope of the claims. The specification is enabling for ex vivo expansion of normal HSCs by administering an rEGFL protein; however, it is not enabling for expansion of MPPs, CMPs, GMPs, or MEPs. The claims recite expansion of more mature progenitor cell types (i.e. CMPs, GMPS, etc.) which are known in the art to have reduced expansion capabilities, but the instant working examples are only directed toward expansion of HSCs. Given numerous other variables that are known in the art to affect expansion and the differences between HSCs and other cell populations within the HSPC lineage, undue experimentation would be required to produce the invention commensurate with the breadth of claims 27 and 29 based on the disclosure of the instant specification and the knowledge in the art.
Furthermore, the specification is not enabling for expansion of HSPCs without a loss of stem potential, as recited in Claim 28. The art teaches that achieving EGFL7-mediated expansion of HSCs without a loss in stem potential is not possible and the specification fails to disclosure how one of ordinary skill in the art would overcome this problem. In view of the discussion above, one of ordinary skill in the art would not be able to use the invention recited in Claim 28 without undue experimentation.
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.
Claims 27 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Beate et al., 2014 (see instant PTO-892), in view of Mahmoud, 2007 (see instant PTO-892).
Claim 27 recites a method of expanding HSPCs by administering to a HSPC a recombinant EGFL7 protein. Claim 29 further limits the cell population to HSCs.
Beate teaches EGFL7-mediated expansion and differentiation of HSCs (abstract). Beate teaches that EGLF7 binds to beta3integrin which ultimately activates the Akt pathway in HSCs (abstract). As evidenced by Kharas et al., 2010 (see instant PTO-892), Akt activation results in short-term HSC expansion and ultimately differentiation (pg. 1410, right side, bottom half of first paragraph).
However, Beate does not teach that EGFL7 was a recombinant protein.
Mahmoud teaches that recombinant proteins were standard in the field of biotechnology at the time of filing. Recombinant protein synthesis enables the production of proteins on demand (abstract) rather than extraction from natural sources (pg. 10, left side, lines 4-6) and is particularly useful for generation of specific protein mutants (pg. 10, right side, three lines from bottom). It also teaches improvements in efficiency for protein synthesis (pg. 18, middle paragraph).
It would have been obvious to one of ordinary skill in the art that the EGFL7 protein used for HSPC expansion, as taught by Beate, could be substituted for a functionally equivalent recombinant EGFL7 protein. One of ordinary skill in the art would have been motivated to use a recombinant EGFL7 protein due to the versatility and efficiency afforded by recombinant protein synthesis. There would be a reasonable expectation of success because substitution of the recombinant protein for the natural counterpart was conventional in the biotechnology sector at the time of filing (Mahmoud, abstract).
Conclusion
No claims allowed.
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/MICHELLE CALLAHAN BUCCINI/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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