Comments on C436-A19 (Proposal)
Correspondence with ECLA
C12N5/077 corresponds to the ECLA groups C12N5/06B6, 5/06B16, 5/06B21 and 5/06B26. This is in line with the fact that all those different skeletal lineages derives from mesenchymal stem cells.
C12N5/0775 corresponds to C12N5/06B21P and 5/06B26P. This grouping is in line with the common assumption that bone marrow-derived mesenchymal stem cells (21P) and adipose-derived stem cells (26P) are similar populations with similar potency, and possibly fully identical.
C12N5/0783 corresponds to the sum of ECLA C12N5/06B11C and 5/06B11N.
Numbering
In the current proposal, most stem cell groups ends in _5, though some occasionally ends in _9 or _7.
Numbering is, of course, fully arbitrary, but one should keep in mind that the division between stem and nonstem is not symmetrical (in the future, further subgroups for differentiated cells may be introduced before the stem cell subgroup, but there is no likelihood that subgroups will ever be introduced after the stem cell subgroup) and that extension space should be reserved for further cell types or tissues not yet introduced in the scheme.
Comments of C436-A20 (JP comments)
A-1) Tumour cells
As pointed out by DE in A.21, tumour cells usually also have the differentiated phenotype of the normal cells they derive from. Tumour cells may thus be of interest either because of their transformed, tumoural, phenotype or because they provide immortalised equivalents of normal cells for in vitro studies. In the former case, tumour cells deserve a sub-group of their own; in the latter case, tumour cells are best considered, and classified, according to their differentiated phenotype. For this reason, experts in the EPO think that the tumour subgroup may well be placed before any differentiated subgroup, with the subgroup for untransformed cells taking precedence where necessary.
The common practice of classifying in these groups of to favour of the most appropriate place based on actual technical content. We respectfully submit that the Last Place Rule is of little help in this technical field, due to the lack of any meaningful "order" of the various cell types or tissues.
However, if other offices believe on preserving the order of subgroups between the IPC proposal and the more detailed ECLA scheme on which it is based, we would reshuffle the ECLA groups to present tumour cells first, then embryonic/foetal cells (which present the same issue of differentiated cells going into the
"adult" groups where appropriate) and finally the various differentiated cells.
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Should tumour cells be placed after any normal somatic cells, we observe that, as also pointed out by DE, the present scheme is far from exhaustive and that space should be reserved for future extension. Of course, new subgroups can be inserted at any place by using more and more digits, but extensions such as
5/076 ... Sperm cells
5/0765 ... Epithelial cells
[5/07655 .... Stem cells]
5/0767 ... Liver cells
[5/07675
5/07677
.... Stem cells; Oval cells]
... Pancreas cells
[5/076785 .... Stem cells]
5/0768 ... Endothelial cells
[5/07685 .... Stem cells]
5/077 ... Mesenchymal cells would be inelegant and unpractical.
Yet it is already foreseen to use (most of) the ranges 5/077x, 5/078x and 5/079x for four-dot subdivisions and, if the scheme is to convey some meaning, it is not suitable to insert normal somatic cells in-between tumour cells, embryonic/foetal cells and germ cells, which means that the range 5/07-5/076 is somewhat "closed" and that the above example is not so remote from what could actually occur in the near future.
Thealternative is to "spill over" the former 5/08 and introduce future three-dot groups as 5/081, 5/083, etc. In that case, tumour cells should be introduced now as 5/09x rather than as 5/0798 ("after 5/0797").
A-2) Non-embryonic pluripotent stem cells
This is a scientifically difficult issue. While the hierarchy makes this group appears with "three dots", we submit that is conceptually more related to the "four dots" groups; accordingly, approval might be deferred at a later stage, and this group should probably be introduced only at advanced level.
(1) The very idea of pluripotent stem cells beyond the embryonic stage is controversial. Accordingly, the
EPO practice is to admit as few documents in ECLA C12N5/06B3 as possible. Convincing evidence of differentiation into at least two of the three broad lineages (ecto-/meso-/endoderm) is required; documents which do not meet this requirement are classified elsewhere as (more committed) stem/progenitors, disregarding unwarranted claims of pluripotency. These are exceptionally stringent requirements, which fit an exceptionally obscure situation, and allowed by the limited number of examiners classifying such documents at the EPO. It is acknowledged that other offices may not want to apply the same stringent requirements and that worldwide harmonisation may be difficult, if not impossible, to achieve.
(2-3) Currently, consistent use of the vocabulary multi-/pluri-/totipotent is not achieved in scientific publications. Patents further tend to indulge in speculation and present an even worse situation. Accordingly, the EPO has defined its own vocabulary in a title note to ECLA C12N5/06: with reference to the broad embryonic lineages (ectoderm, mesoderm, ectoderm, plus "extra-embryonic" trophectoderm), "multipotent" refers to multiple potency within one lineage (e.g. MSC differentiating to bone, cartilage or adipous tissue) and "pluripotent" to potency towards at least two lineages (e.g. differentiating to neuron, bone or pancreas).
"MASC", given as example in the title of ECLA C12N5/06B3, refers to the cell population so designed by Pr.
Catherine Verfaillie et al. in WO 01/11011 and further publications, which were arguably the best example
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of "non-embryonic pluripotent stem cells" (with a demonstrated ability to differentiate to all lineages) available at the time this subgroup was introduced into ECLA. It is NOT intended to refer to any other cell population, nor even to consider the original meaning of the acronym "MASC". That Pr. Verfaillie has used the word "multipotent" where most authors (and the EPO) use "pluripotent" illustrates the extent of the vocabulary issue.
Regardless of any precise wording, it should be reasonably obvious that the "MASC" cell population is covered by the proposed IPC C12N5/074; however, in view of possible confusion as pointed out by JP comments, it may well be better not to introduce it as an example.
Comments on C436-A21 (DE comments) a) Tumour cells and Last Place Rule see our above comment. c) The EPO agrees that the proposed scheme is incomplete (no scheme will ever be), but the individual subgroups should be clear (with the possible exception of C12N5/074) and accordingly, the scheme is understandable. While attempts can be made to regroup some cell types based on their functional or developmental relationship, any scheme is eventually little more than a list of cell types in arbitrary order.
The ECLA scheme is historically based on a "static" approach of dividing the (adult) body into organs and tissues; aspects related to stem cells were added later, so stem cells generally appear as 5/06BxP subdivision of the relevant 5/06Bx tissue or cell type. The German proposal is based on a different, "dynamic", view of the developing body. "From undifferentiated to differentiated" makes sense only under this approach.
We have however practical reservations:
* "Static" histology is better described and understood than "dynamic" developmental biology, so the former should provide a safer and more stable basis for classification than the latter.
* The developmental approach adds one unnecessary layer of complexity to the scheme for the purpose of classifying basic technology for cell culture without differentiation. This new approach fits better with technology based upon differentiation, with a prospective view to regenerative medicine, but does not appear to add useful information as to the source of the mobilised stem cell ("regular" stem cells for the target organ? other stem cells through transdifferentiation? pluripotent adult stem cells?). Since applications pertaining to differentiation and/or regenerative medicine have in any case a target cell type, tissue or organ, they can be classified accordingly along the lines of a “static” scheme. The EPO cannot identify any benefit from a
“dynamic” approach to the classification scheme.
* Under this scheme, normal tissues and cell types are 4-dot subgroups of the 3-dot stem cell groups, so it is not possible to discuss the stem cell groups separately from, or at a different level than, the rest of the scheme.
Looking into the details of the proposed scheme, the EPO has further comments or questions.
* It is to be reminded that the so-called “embryonic stem cells” (ES) are a laboratory artefact . While there must be pluripotent stem cell at embryonic stage, they do no exhibit what has now been characterised as the
ES phenotype. Physiologically normal embryonic cell are thus placed hierarchically below a laboratory artefact, which is questionable.
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* No clear-cut distinction between embryo and foetus exists. There would be a need for a definition here. But, fundamentally, it should be asked what would be the purpose of such a distinction for the purpose of classification. Differentiated foetal cells can be classified alongside adult cells wherever possible. Those cells or tissue which cannot be classified as adult cells are the trophectoderm lineage (placenta, amnion, etc.;
ECLA group C12N5/06B2L), which by nature are no longer present after birth, and the transient structures of early embryonic development, the precise classification of which would go beyond the requirements of the Advanced level.
* At point c), the DE proposal makes a connection between embryonic, foetal and adult stem cells and decreased developmental potential, from totipotent to multipotent. Accordingly, the scheme distinguishes at point d) between totipotent or pluripotent embryonic stem cells, pluripotent or multipotent foetal stem cells and only multipotent adult stem cells. Do we read correctly that, in the view of the DPMA, any pluripotent cell found in the adult must be “left-over” from embryonic or foetal stage and that it is intended to replace the proposed C12N5/074 by the “foetal stem cell” group? This is a possible assumption, but a rather bold one, and it would be dangerous to base an IPC scheme onto an unproven hypothesis.
* “Endothelial” should probably read “ vascular endothelial”. Where do haemangioblast cells fall ? (i.e. those cells presumed to be progenitors to both haematopoietic cells, including haematopoietic stem cells, and vascular endothelium)
* Adult epithelia are a plurality of developmentally unrelated tissues. For instance, skin derives from the embryonic ectoderm, but digestive epithelium derives from the embryonic endoderm. As ECLA currently has a comparable hierarchy covering all epithelia (C12N5/06B12 and subgroups), it has been found that this arrangement is inconvenient and that each and every distinct epithelium could warrant its own dedicated stem cell group.
* The German proposal introduces three distinct hierarchies for cartilage, fat and skeletal muscle. There is no obvious place for bones, nor for (non-haematopoietic) bone marrow stroma, nor for mesenchymal stem cells as found in bone marrow and adipose stroma. As far as is currently known, there are no stem cell in cartilage itself, new cells migrate in from bone marrow, and possibly from the very same stem cell population which gives rise to fat cells and to the bone itself. The scheme appears developmentally incorrect here.
* Generally, the German proposal does not provide an obvious place to classy differentiated cells not explicitly foreseen in the scheme.
Comments on C436-A22 (US comments)
1. LPR
We appreciate the willingness of other offices to harmonise using ECLA using as a basis.
As far as C12N5 is concerned, the last place rule is actually no longer applied in ECLA.
It would not make sense to place tumour cells in between groups of normal cells, but they can be placed indifferently before or after the block of all normal cells. For historical reasons, they appear in ECLA after normal cells.
If tumour cells are placed before normal cells, further extension of the tumour cell group is numerically constrained, but not the extension of normal cell groups. It is unlikely that much extension will ever be required for tumour cells. On the contrary, the current proposal is far from exhaustive with respect to normal cells; a need to further extend the scheme for normal cells is foreseeable, and should be anticipated.
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For this practical reason, we suggest to place tumour cells before normal cells in the IPC scheme, leaving as much extension space as possible.
Whatever order is elected, no actual reclassification of documents would be necessary because the last place rule has not been applied during the last reorganisation.
2. Note exists in C12N 5/06B4
This subject-matter indeed used to be in ECLA A01K67/027, but has since been transferred to
C12N15/87C+. Notes in C12N5 have been overlooked in the process and this will be corrected in ECLA.
3. Desirability and correctness of the proposed four-dot groups
"Mesenchymal" is an umbrella term for many different tissues, mostly the skeleton and skeletal muscles, which all appear to derive from common stem cell populations. In terms of development, mesenchyme derives from (but does not equates with) the embryonic mesoderm.
A muscle fiber, an adipous cell, a chondrocyte, a bone marrow stroma cell are all mesenchymal cells, but only about one non-haematopoietic bone marrow cell out of 100,000 is possibly a mesenchymal stem cell.
As proposed, IPC C12N5/077 brings together ECLA C12N5/06B6+, 06B16, 06B21 and 06B26, while IPC
C12N5/0775 merges together ECLA C12N5/06B21P and 06B26P.
This is indeed a different approach to the one adopted by ECLA. Both approaches make sense, the current
ECLA approach more from an anatomical point of view, the proposed IPC approach more from a developmental point of view.
Considering that ECLA C12N5/06B18P and 06B20P are of very little use, as well as C12N5/06B6P since myoblasts have been rolled into C12N5/06B6K alongside mature muscular fibers, and that no
"C12N5/06B16P" has even been proposed, there might be a case for regrouping the scattered ECLA groups pertaining to mesenchymal cells.
4. Inclusion of “progenitor cells”
We think indeed that the progenitor cells are to be classified in 5/0781, 5/0783, and that 5/0784 are unipotent since all multipotent varieties should be classified in 5/0789.
This is in line with practice in ECLA C12N5/06B11 (See Note after group title:
Note: Commited progenitors are classified with their progeny)
The reason is that the cascade of differentiation in blood cells is complex but also relatively well described, and probably better understood than simpler differentiation routes in solid organs. It makes more sense to group committed pre-B with mature and immature B cells, pre-T with T cells, etc. than mixing unipotent progenitors/precursors with bi- or multipotent precursors and stem cells.
For historical reasons, committed progenitors other than haematopoietic progenitors and myocytes progenitors are still classified in ECLA in the relevant C12N5/06BnP group, alongside the less comitted progenitors and stem cells.
Consistency in the overall scheme should indeed be of concern. At this point, we see only an issue with neural progenitors in proposed IPC C12N5/0797. Committed neuron precursors may indeed by grouped with neurons.
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5. Should the titles of the 3 dot groups under C12N 5/071+ need to made broader to include other than just the differentiated cell name
"Neural cell" should spontaneously include all kinds of neural cells, including lineage-restricted stem/progenitor/precursors.
DE's concern appears to derive from a completely different philosophy underlying their own counterproposal. The proposed IPC roughly follows what ECLA currently is, i.e. it divides first the body into organs or tissues and then look into the (most relevant) cells types of these tissues; in this view, lineage-restricted stem cells are one cell type from said lineage, alongside the corresponding terminally differentiated cells.
The DE counter proposal follows development, putting stem cells at top of hierarchies and terminally differentiated cells at the bottom.
Again, both approaches make sense. We submit however that the ECLA approach seems to be more robust because our understanding of anatomy and histology is not likely to face a major challenge, while our understanding of development is continually challenged by new findings from ongoing research.
Bertrand Teyssier
Anne Glanddier.
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